27836 Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations concludes that the proposed use of the (address above) between 9 a.m. and 4 document. Any objections received in additive is safe, that the additive will p.m., Monday through Friday. response to the regulation may be seen achieve its intended technical effect, Any person who will be adversely in the Dockets Management Branch and therefore, that the regulations in affected by this regulation may at any between 9 a.m. and 4 p.m., Monday § 178.2010 should be amended as set time on or before June 22, 1998, file through Friday. forth below. with the Dockets Management Branch List of Subjects in 21 CFR Part 178 In accordance with § 171.1(h) (21 CFR (address above) written objections thereto. Each objection shall be Food additives, Food packaging. 171.1(h)), the petition and the Therefore, under the Federal Food, documents that FDA considered and separately numbered, and each numbered objection shall specify with Drug, and Cosmetic Act and under relied upon in reaching its decision to authority delegated to the Commissioner approve the petition are available for particularity the provisions of the regulation to which objection is made of Food and Drugs and redelegated to inspection at the Center for Food Safety the Director, Center for Food Safety and and Applied Nutrition by appointment and the grounds for the objection. Each numbered objection on which a hearing Applied Nutrition, 21 CFR part 178 is with the information contact person amended as follows: listed above. As provided in § 171.1(h), is requested shall specifically so state. the agency will delete from the Failure to request a hearing for any PART 178ÐINDIRECT FOOD documents any materials that are not particular objection shall constitute a ADDITIVES: ADJUVANTS, available for public disclosure before waiver of the right to a hearing on that PRODUCTION AIDS, AND SANITIZERS objection. Each numbered objection for making the documents available for which a hearing is requested shall 1. The authority citation for 21 CFR inspection. include a detailed description and part 178 continues to read as follows: The agency has carefully considered analysis of the specific factual Authority: 21 U.S.C. 321, 342, 348, 379e. the potential environmental effects of information intended to be presented in 2. Section 178.2010 is amended in the this action. FDA has concluded that the support of the objection in the event table in paragraph (b) by alphabetically action will not have a significant impact that a hearing is held. Failure to include adding a new entry under the headings on the human environment, and that an such a description and analysis for any ‘‘Substances’’ and ‘‘Limitations’’ to read environmental impact statement is not particular objection shall constitute a as follows: required. The agency’s finding of no waiver of the right to a hearing on the significant impact and the evidence objection. Three copies of all documents § 178.2010 Antioxidants and/or stabilizers supporting that finding, contained in an shall be submitted and shall be for polymers. environmental assessment, may be seen identified with the docket number * * * * * in the Dockets Management Branch found in brackets in the heading of this (b) * * *

Substances Limitations

******* 1, 11-(3, 6, 9-Trioxaundecyl) bis-3-(dodecylthio) propionate (CAS Reg. For use only as provided in § 175.300(b)(3)(xxxi) of this chapter at 4.0 No. 64253±30±1). parts per 100 parts rubber. *******

Dated: May 11, 1998. DEPARTMENT OF HEALTH AND sodium phosphate oral solution) to not L. Robert Lake, HUMAN SERVICES greater than 90 milliliters (mL) (3 Director, Office of Policy, Planning and ounces (oz)) when used as an over-the- Strategic Initiatives, Center for Food Safety Food and Drug Administration counter (OTC) laxative drug product. and Applied Nutrition. FDA is limiting the container size 21 CFR Part 201 [FR Doc. 98–13469 Filed 5–20–98; 8:45 am] because of reports of deaths associated BILLING CODE 4160±01±F [Docket No. 78N±036L] with an overdosage of sodium RIN 0910±AA01 phosphates oral solution when the product was packaged in a larger-size Package Size Limitation for Sodium container and a larger than intended Phosphates Oral Solution and Warning dose was ingested inadvertently. The and Direction Statements for Oral and agency is also requiring warning and Rectal Sodium Phosphates for Over- direction statements to inform the-Counter Laxative Use consumers that exceeding the AGENCY: Food and Drug Administration, recommended dose of oral and rectal HHS. sodium phosphates products in a 24- ACTION: Final rule. hour period can be harmful. This final rule is part of the ongoing review of SUMMARY: The Food and Drug OTC drug products conducted by FDA. Administration (FDA) is issuing a final DATES: rule to limit the container size for The regulation is effective June sodium phosphates oral solution 22, 1998, however compliance with (dibasic sodium phosphate/monobasic Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations 27837

§ 201.307(b)(2) and (b)(3) is not regimen in preparing a patient for sodium phosphates oral solution creates mandatory until September 18, 1998. surgery or for preparing the colon for x- a potential safety risk, particularly for FOR FURTHER INFORMATION CONTACT: ray or endoscopic examination. (See elderly persons who are likely to use the Cheryl A. Turner, Center for Drug proposed § 334.80(a)(2), 50 FR 2124 at product for bowel cleansing prior to Evaluation and Research (HFD–560), 2157.) Sodium phosphates oral solution surgery or a diagnostic procedure Food and Drug Administration, 5600 and sodium phosphates enema 3, involving the colon. Because of the Fishers Lane, Rockville, MD 20857, respectively, are the current United reported cases of accidental overdosing 301–827–2222. States Pharmacopeia (USP) names for and the confusion that has occurred SUPPLEMENTARY INFORMATION: the oral and rectal dosage forms of the between 240-mL and 90-mL container combination of sodium phosphates sizes, the agency proposed that the 240- I. Background ingredients. mL size container of sodium phosphates In the Federal Register of March 21, In the Federal Register of March 31, oral solution should no longer remain in 1975 (40 FR 12902), FDA published, 1994 (59 FR 15139), the agency the OTC marketplace. In the interest of under § 330.10(a)(6) (21 CFR proposed to amend the tentative final safety, the agency proposed to limit the 330.10(a)(6)), an advance notice of monograph for OTC laxative drug maximum OTC container size for this proposed rulemaking to establish a products to limit the OTC container size product to 90 mL. monograph for OTC laxative, for sodium phosphates oral solution to The agency proposed to include the antidiarrheal, emetic, and antiemetic not greater than 90 mL. The agency also package size limitation and warning in drug products, together with the proposed a warning for all oral and the monograph for OTC laxative drug recommendations of the Advisory rectal dosage forms of sodium products. However, that monograph has Review Panel on OTC Laxative, phosphates products to inform not been finalized to date. Because of Antidiarrheal, Emetic, and Antiemetic consumers not to exceed the the potential safety risk involved, the Drug Products (the Panel), which was recommended dosage unless directed by agency has decided to finalize both the the Advisory Review Panel responsible a doctor. Interested persons were package size limitation and several new for evaluating data on the active invited to submit written comments on warning and direction statements prior ingredients in these classes. The Panel the proposed regulation and on the to completion of the final monograph recommended monograph status for agency’s economic impact for OTC laxative drug products. The phosphate salts, such as sodium determination by May 31, 1994. agency has decided to include this phosphates oral solution (40 FR 12902 In response to the proposal, two information in part 201 (21 CFR part at 12940), but did not recommend any manufacturers of laxative drug products 201) at this time and to incorporate it container size limitations. submitted comments. Neither comment into the final monograph for OTC The agency’s proposed regulation, in addressed the agency’s economic impact laxative drug products at a later date. the form of a tentative final monograph, determination. Copies of these In the Federal Register of February for OTC laxative drug products was comments are on public display in the 27, 1997 (62 FR 9024), FDA proposed to published in the Federal Register of Dockets Management Branch (HFA– establish a standardized format for the January 15, 1985 (50 FR 2124). The 305), Food and Drug Administration, labeling of OTC drug products. Until the agency also proposed monograph status 12420 Parklawn Dr., rm. 1–23, proposal is finalized, manufacturers, for sodium phosphates oral solution (50 Rockville, MD 20857. Additional distributors, and packagers must comply FR 2124 at 2152 and 2155), but did not information that has come to the with the final rule published herein and recommend any container size agency’s attention since publication of all other currently applicable labeling limitations. The agency proposed the the proposal is also on public display in regulations. The agency will eventually following dosage for sodium phosphates the Dockets Management Branch. use the final labeling rule to incorporate oral solution for adults and children 12 In the proposal, the agency discussed the information included herein in part years of age and over: 3.42 to 7.56 grams its reasons for limiting the package size 201 into the final monograph for OTC (g) of dibasic sodium phosphate and 9.1 for sodium phosphates oral solution (59 laxative drug products. to 20.2 g of monobasic sodium FR 15139). The agency noted that the 1 II. The Agency’s Conclusions on the phosphate in a single daily dose. (See major trade product containing sodium Comments proposed § 334.58(d)(5)(i) (21 CFR phosphates oral solution was marketed 1. One comment stated that, according 334.58(d)(5)(i)), 50 FR 2124 at 2155.) In in 45-mL, 90-mL, and 240-mL bottles. addition to its use as an OTC laxative to the USP 22 (Ref. 1), the current The purgative dose or dose used for terminology for sodium phosphate is for the relief of occasional constipation, colonoscopy is 45 mL. Because the 2 monobasic sodium phosphate and for sodium phosphates oral solution is product was available in three sizes, the used as part of a bowel cleansing sodium biphosphate it is dibasic sodium manufacturer’s labeling advised phosphate. The comment stated that the physicians to prescribe by volumes and 1 tentative final monograph should be In the tentative final monograph for OTC not to prescribe by the bottle and not to laxative drug products, published in the Federal amended accordingly. Register of January 15, 1985 (50 FR 2124), and in exceed the recommended dosage, as Under agency regulations in 21 CFR the proposed rule for package size limitation for serious side effects may occur. Despite 299.4(e), the established name of a drug OTC laxative drug products published in the this labeling, the multiple container is the current compendial name or the Federal Register of March 31, 1994 (59 FR 15139), sizes available in the marketplace have the agency referred to dibasic sodium phosphate as USAN (U.S. Adopted Names Council) ‘‘sodium phosphate,’’ and monobasic sodium caused consumer confusion and appear adopted name listed in the USP phosphate as ‘‘sodium biphosphate.’’ The current to have been involved in several Dictionary of USAN and International nomenclature in the USP Dictionary of USAN and consumer deaths. Drug Names. Both the U.S. International Drug Names, 1997 is ‘‘dibasic sodium The agency determined that the OTC phosphate’’ and ‘‘monobasic sodium phosphate,’’ Pharmacopeia 23/National Formulary respectively. This final rule uses the current availability of the 240-mL container of 18 (Ref. 2) and the USP Dictionary of nomenclature. USAN and International Drug Names, 2Sodium phosphates oral solution is the official 3 Sodium phosphates enema is the official name name for a solution of dibasic sodium phosphate for a solution of dibasic sodium phosphate and 1997 (Ref. 3) list the current name for and monobasic sodium phosphate in the U.S. monobasic sodium phosphate in the U.S. sodium phosphate as ‘‘dibasic sodium Pharmacopeia 23/National Formulary 18, 1995. Pharmacopeia 23/National Formulary 18, 1995. phosphate,’’ and for sodium 27838 Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations biphosphate as ‘‘monobasic sodium involved confusion resulting from the a larger size container (90 mL) may be phosphate.’’ (See footnote 1, supra.) It availability of a 240-mL container size more convenient for consumers to appears that the comment inadvertently (59 FR 15139). (In 1993, the purchase and have available for future reversed the names of the ingredients. manufacturer of the major trade product use. The agency is also aware that the 2. One comment stated that the containing this solution ceased 45-mL and 90-mL container sizes are agency’s proposal that the final rule be manufacture and initiated a market often recommended and prescribed by effective 30 days after its publication in withdrawal of the 240-mL container physicians for bowel cleansing prior to the Federal Register is insufficient time. size.) The oral solution is currently surgery and diagnostic procedures of the The comment argued that 30 days marketed in 45-mL and 90-mL colon. Accordingly, the agency is would not be enough time for relabeling containers. The agency has not received allowing the 90-mL container of sodium of its sodium phosphates products and any reports that a one-time 90 mL dose phosphates oral solution to remain on requested that the final rule be effective has resulted in a death or a serious the OTC market. However, in an effort 120 days after its publication in the adverse reaction requiring medical to prevent consumers from taking an Federal Register. treatment. entire 90-mL container in 1 day (24 The agency is instituting a split The agency has reviewed the hours), the agency is adding additional effective date for this final rule. Because submitted data (Refs. 4, 5, and 6) and statements in the directions in of the potential serious safety risk agrees that taking more than 45 mL of § 201.307(b)(3)(ii) to inform consumers involved, the agency has determined sodium phosphates solution over a 10- how much of the oral solution may be that initial introduction or initial to 12-hour period can result in taken as a single daily dose and not to delivery for introduction into interstate significant changes in electrolytes and take more than the recommended daily commerce of any container size of may impose a risk of serious injury. (See dose in a 24-hour period. The agency sodium phosphates oral solution greater comment 4 in section II of this has also revised the format for stating than 90 mL should cease as soon as document.) Therefore, the agency is children’s ages from that proposed in possible (within 30 days of this final requiring specific warning and direction § 334.58(d)(5)(i) of the tentative final rule). However, the agency concurs with statements to ensure that the correct monograph (50 FR 2124 at 2155). The the comment that manufacturers need dose is used and that consumers do not directions now state: more than 30 days to relabel these drug use more than the recommended dose in Adults and children 12 years of age and products and is granting the 120 days a 24-hour period. The agency proposed over: Oral dosage is dibasic sodium requested by the comment. Because of to amend the tentative final monograph phosphate 3.42 to 7.56 grams (g) and the potential serious safety risks, the for OTC laxative drug products to monobasic sodium phosphate 9.1 to 20.2 g agency has determined that include in § 334.58(c)(2)(iv) the (20 to 45 mL dibasic sodium phosphate/ manufacturers need to work promptly to following warning for oral and rectal monobasic sodium phosphate oral solution) relabel their products. The agency is as a single daily dose. ‘‘Do not take more than dosage forms of sodium phosphates 45 mL (9 teaspoonfuls or 3 tablespoonfuls) in providing manufacturers the option to products: ‘‘Do not exceed recommended a 24-hour period.’’ use supplementary labeling (e.g., stick- dose unless directed by a doctor. Children 10 and 11 years of age: Oral on labeling) to add the new warning and Serious side effects many occur from dosage is dibasic sodium phosphate 1.71 to direction information to currently excess dosage’’ (59 FR 15139). 3.78 g and monobasic sodium phosphate 4.5 manufactured products not yet In this final rule, the agency is to 10.1 g (10 to 20 mL dibasic sodium introduced into interstate commerce or revising the proposed warning by phosphate/monobasic sodium phosphate oral on package labeling that has not yet adding 24-hour dosing information and solution) as a single daily dose. ‘‘Do not take been incorporated into the by simplifying the language. The agency more than 20 mL (4 teaspoonfuls) in a 24- hour period.’’ manufacturing process. If manufacturers is also requiring separate warnings for Children 5 to 9 years of age: Oral dosage choose not to use stick-on labeling, they oral and rectal enema drug products. is dibasic sodium phosphate 0.86 to 1.89 g are encouraged to have new labeling For oral sodium phosphates drug and monobasic sodium phosphate 2.2 to 5.05 containing the new warning and products, the new warning states: g (5 to 10 mL dibasic sodium phosphate/ direction information printed as ‘‘Taking more than the recommended monobasic sodium phosphate oral solution) expeditiously as possible in the interest dose in 24 hours can be harmful.’’ For as a single daily dose. ‘‘Do not take more than of safe use of these products. rectal sodium phosphates drug 10 mL (2 teaspoonfuls) in a 24-hour period.’’ 3. One comment stated that sodium products, the new warning states: Children under 5 years of age: ask a doctor. The agency notes that the directions phosphates oral solution should not be ‘‘Using more than one enema in 24 for sodium phosphates oral solution marketed in packages containing more hours can be harmful.’’ Both warnings contain separate dosages for children 10 than 45 mL. The comment argued that must be in boldface type and appear as and 11 years of age and for children 5 45 mL of this product equals the ‘‘single the first statement under the heading to 9 years of age. These age ranges are daily dose’’ of solution generally ‘‘Warnings.’’ (See comment 5 in section not consistent with age ranges used for recognized as safe and effective for use II of this document.) as a laxative and bowel cleansing agent The agency is also adding new the majority of OTC laxative drug in the tentative final monograph. The directions in boldface type immediately products, which recommend dosages for comment provided data to show that preceding the dosage information, children 6 to 11 years of age. Therefore, taking more than this amount has been which state: ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) elsewhere, in this issue of the Federal shown to cause significant changes in ‘‘more unless directed by a doctor. See Register, the agency is proposing to blood levels of sodium, potassium, Warnings.’’ (See comment 4 in section revise the directions for sodium phosphate, chloride, and calcium, II of this document.) The new directions phosphates oral solution to limit the thereby imposing a risk of serious injury appear in § 201.307(b)(3)(i). OTC use of these products to children (Refs. 4, 5, and 6). The agency notes that sodium 6 years of age and above. The agency does not agree with the phosphates oral solution is available for The proposed directions state: ** * Children 6 to 9 years of age: Oral comment that packages containing more general laxative use for relief of dosage is dibasic sodium phosphate 0.86 to than 45 mL of sodium phosphates oral occasional constipation at a single daily 1.89 g and monobasic sodium phosphate 2.2 solution should not be marketed. dose of 20 mL to 45 mL for adults and to 5.05 g (5 to 10 mL dibasic sodium Problems that previously occurred children 12 years of age and over. Thus, phosphate/monobasic sodium phosphate oral Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations 27839 solution) as a single daily dose. ‘Do not take episode’’ occurred in the sodium of the small sample size, the fact that more than 10 mL (2 teaspoonfuls) in a 24- phosphates group. The authors none of the study subjects died or had hour period.’ Children under 6 years of age: mentioned that the subject’s vital signs serious side effects that required ask a doctor. did not appear to indicate that hospitalization cannot be interpreted to 4. One comment requested that hypovolemia (abnormally decreased mean that two 45-mL doses of sodium sodium phosphates oral solution volume of circulating plasma) was the phosphates oral solution are safe to products bear a warning against cause. The authors reported that ingest without a physician’s consuming more than 45 mL in a 24- hyperphosphatemia occurred with supervision. hour period unless directed by a sodium phosphates, but serum Warner and DiPalma (Ref. 6) stated physician. The comment contended that phosphate values returned to normal that sodium phosphates oral solution is there are potentially serious health within 24 hours, and no concomitant extremely popular for use as a bowel problems associated with high doses of decrease in calcium was seen. They cleansing agent because it is effective, this product. The comment submitted added that histological assessment for easy to administer, and well tolerated. data to show that consuming more that possible preparation-induced changes However, they contended that little data 45 mL of sodium phosphates oral revealed no difference between the two are available concerning its safety. They solution in 24 hours has resulted in drugs. mentioned that the majority of trials significant changes in blood levels of The agency notes that numerous evaluating the product for use as a sodium, potassium, phosphate, induced electrolyte abnormalities bowel cleanser have not systematically chloride, and calcium, thereby imposing occurred in this study. The data showed monitored electrolytes. They asserted a risk of serious injury (Refs. 4, 5, and statistically significant decreases in that the solubility product of calcium 6). potassium and increases in hematocrit, and phosphate, when exceeded, leads to The agency has reviewed the sodium, chloride, osmolality, and soft tissue calcification in areas where submitted data and agrees that ingesting phosphate. Extreme serum phosphate an alkaline internal environment more that 45 mL of sodium phosphates levels reached 11.6 milligrams/deciliter enhances calcium phosphate salt oral solution in a 24-hour period may be (mg/dL) in the sodium phosphates deposit, primarily in the kidneys, heart, harmful. Clarkston et al. (Ref. 4) group and 4.7 mg/dL in the PEG group; blood vessel, cornea, lungs, and gastric compared a polyethylene glycol (PEG) normal values are 2.5 to 4.1 mg/dL. In mucosa. They stated that the normal based gastrointestinal lavage to a hyperphosphatemia, excessive calcium-phosphate product is 40 mg/dL, sodium phosphates oral regimen. In this complexing of calcium with phosphate which is tightly regulated through randomized trial, 26 subjects took 4 may contribute to a decrease in plasma absorption, excretion, and intracellular/ liters (L) of the PEG solution and 25 ionized calcium, which results in extracellular ion shifts; and that the in subjects took two 45-mL doses of hypocalcemia. Calcium levels were not vitro solubility product of calcium is 58 sodium phosphates oral solution 11 reported for the entire sodium mg/dL, well above the normal value hours apart. The subjects had a phosphates group nor was the risk of (Ref. 6). Warner and DiPalma mentioned chemistry panel and ionized calcium hypokalemia mentioned. The agency that Vanner et al. (Ref. 5) and Kolts (Ref. done prior to taking the drug and on the notes that the postural changes in pulse, 7) have presented limited data to show morning of the colonoscopy. The results systolic blood pressure, and the one phosphate levels rising to as high as 7 indicated that the sodium phosphates ‘‘syncopal episode’’ were most likely mg/dL with relatively unchanged serum solution caused a decrease in ionized due to decreased intravascular volume calcium values. According to Warner serum calcium and serum potassium, in subjects in the sodium phosphates and DiPalma, the increase in phosphate with concomitant increases in group. levels appeared quite transient, but phosphate. The investigators stated that Because elevated phosphate levels are because sampling was so infrequent, it the sodium phosphates oral regimen known to occur with sodium is impossible to ascertain whether even resulted in statistically significant phosphates use, 15 subjects were these high values represent the peak changes in serum sodium, potassium, randomly selected to have serum phosphate concentrations after phosphorus, and calcium (p < 0.01). The phosphate and calcium levels measured administration of sodium phosphates investigators concluded that the risk of at 4 p.m. on the day of colonoscopy and oral solution. symptoms of hypocalcemia must be at 8 a.m. the following day. Seven of the Kolts (Ref. 8) responded to Warner considered due to the abnormal low fifteen subjects received the sodium and DiPalma, and argued that sodium levels of ionized calcium that frequently phosphates regimen. Vanner et al. phosphates oral solution should be the occur with this regimen. reported that 2 hours after the second preparation of choice for most Vanner et al. (Ref. 5) compared a dose, the mean serum phosphorus was endoscopy outpatients due to its low standard PEG based gastrointestinal 7.2 mg/dL (nearly twice the pre-study cost, comfort for the patient, and low solution to a sodium phosphates oral value of 3.7 mg/dL), while the total incidence of adverse side events. Kolts solution prior to colonoscopy. In this calcium values continued to decline for stated that the sodium phosphates oral parallel, single-blinded, randomized at least 24 hours after the dose was solution used in his study (Ref. 7) had study, 54 subjects received two 45-mL taken. been sold OTC for more than 100 years doses of the sodium phosphates oral The agency believes that the Vanner and the manufacturer had not reported solution 11 hours apart, and 48 subjects et al. study showed that postural any serious side effects, except when received 4 L of the PEG solution. The increases in pulse, decreases in systolic the solution was taken in massive subjects had blood tests on admission blood pressure, and serum electrolyte overdoses or if used when and the morning of the procedure. The and plasma volume shifts were greater contraindicated. Kolts added that there authors concluded that the sodium in the sodium phosphates group than in were no reports of adverse events such phosphates oral solution was safe and the PEG group. The incidence of as ectopic calcification in the literature effective because serial measurements of postural elevation in heart rate, from 1966 to 1993 from the use of blood tests, postural pulse, and blood indicating significant reduction in phosphate catharsis in people with pressure changes did not reveal any intravascular volume, was also three normal renal function. Kolts concluded clinically significant changes in times higher in the sodium phosphates that his (Ref. 7) and Vanner’s (Ref. 5) intravascular volume. One ‘‘syncopal group than in the PEG group. Because studies documented the minor changes 27840 Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations in clinically relevant electrolytes as well following warning in § 201.307(b)(2)(i) of the amount of dibasic sodium as the lack of adverse symptoms from for oral products that contain sodium phosphate per 100 mL. It should have sodium phosphates oral solution. phosphates: ‘‘Taking more than the been approximately 6 g/mL which is The agency finds that the data show recommended dose in 24 hours can be consistent with USP 23 (Ref. 2), which that sodium phosphates oral solution harmful.’’ The sentence is required to states that each 100 mL of sodium can cause alterations in serum levels of appear in boldface type as the first phosphates enema solution contains not sodium, potassium, phosphate, statement under the heading less than 5.7 g and not more than 6.3 g chloride, and calcium. In some people, ‘‘Warnings.’’ The agency is also of dibasic sodium phosphate. such changes can be life-threatening. requiring in § 201.307(b)(3)(i) that the The agency is aware of numerous The agency has particular concerns directions for oral and rectal sodium reports of misuse of sodium phosphates about hypocalcemia occurring due to its phosphates products contain the enemas that resulted in adverse effects reported frequency when two 45-mL following statements in boldface type (Refs. 12 through 23). Wason et al. (Ref. doses of sodium phosphates oral immediately preceding the dosage 12) reported the case of a normal 5- solution are given over a 24-hour information: ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) month-old child who was given an period. The reduction of calcium levels ‘‘more unless directed by a doctor. See entire adult sodium phosphates enema reflects changes in ionized calcium (Ref. Warnings.’’ (See comment 5 in section by her mother. Within 30 minutes, the 9). Hypocalcemia with subsequent low II of this document.) These additional child became extremely ill; levels of ionized calcium may result in statements are intended to refer consciousness decreased; and shock, neuromuscular irritability, heart block, consumers to the warnings when they hyperphosphatemia, hypocalcemia, and and cardiovascular failure (Ref. 9). read the directions for the product. acidosis developed. The child was In the tentative final monograph for 5. One comment disagreed with the hospitalized and responded to OTC laxative drug products (50 FR 2124 proposed warning in § 334.58(c)(2)(iv) intravenous (IV) fluid replacement and at 2155), the agency proposed a for rectal enema sodium phosphates aluminum hydroxide gel. Oxnard, maximum single daily oral dose of 7.56 drug products, which states: ‘‘Do not O’Bell, and Grupe (Ref. 13) reported that g of dibasic sodium phosphate and 20.2 exceed recommended dose unless a 4-year-old child with chronic renal g of monobasic sodium phosphate. The directed by a doctor. Serious side effects failure became profoundly major manufacturer of sodium may occur from excess dosage.’’ The hyperphosphatemic and hypocalcemic phosphates products recommends (as comment argued that the agency after receiving an entire adult sodium part of a bowel cleansing regimen in provided no concrete or specific phosphates enema. The child developed preparation for surgery or preparation of evidence to support this warning. The muscle twitching, acidosis, severe the colon for x-ray or endoscopic comment stated that its sodium diarrhea, and tachycardia, and was examination) (Ref. 10) that 45 mL be phosphates enema contains 19 g/118 mL hospitalized, subsequently responding given at 7 p.m. and again at 6 a.m. the (equivalent to 16 g/100 mL) of to IV calcium gluconate, calcium following morning. The agency notes monobasic sodium phosphate and 7 g/ chloride, and sodium bicarbonate. that 0.9 g/5 mL of dibasic sodium 118 mL (equivalent to 7 g/100 mL) of Other authors have reported that phosphate is equivalent to 17.1 to 18.9 dibasic sodium phosphate. In contrast, children (4 months to 2 1/2 years old) g/100 mL of sodium phosphates oral the oral product contains 2.4 g/5 mL with gastrointestinal anomalies, such as solution, and that 2.4 g/5 mL of (equivalent to 48 g/100 mL) of Hirschsprung’s disease (congenital monobasic sodium phosphate is monobasic sodium phosphate and 0.9 g/ megacolon), and chronic renal failure equivalent to 45.6 to 50.4 g/100 mL of 5 mL (equivalent to 18 g/100 mL) of were at high risk for complications after sodium phosphates oral solution dibasic sodium phosphate. The the use of sodium phosphates enemas according to the USP 23 (Ref. 2). comment stated that because the (Refs. 13 through 20). These children Therefore, over an 11-hour period, 90 phosphate concentration of the enema is received varying amounts of adult or mL of solution (approximately 16.2 g of only one-third that of the oral product, pediatric sodium phosphates enemas for dibasic sodium phosphate and 43.2 g of use of the enema is not likely to result constipation and bowel cleansing prior monobasic sodium phosphate) in overdosage. The comment added that to surgery. Three of the children had containing 9.9 g of sodium could be an overdosage is unlikely to occur due cardiac arrest after the use of hypertonic consumed. The manufacturer of this to the way enemas are used and the sodium phosphates enemas (Refs. 17, product has not submitted sufficient results they produce. The comment 19, and 20). Martin et al. (Ref. 19) data to demonstrate the safety of more mentioned that the enema product is reported that an 11-month-old child than 45 mL of this solution in a 24-hour clearly labeled ‘‘Not intended for oral died after receiving four adult sodium period (Ref. 11). Thus, the agency consumption,’’ and that the current phosphates enemas. Loughnan and concludes that the safe oral use of more labeling clearly states the appropriate Mullins (Ref. 17) reported that a 9- than 7.56 g of dibasic sodium phosphate dosage. Thus, the comment concluded month-old child suffered severe and and 20.2 g of monobasic sodium that the warning should not be required permanent brain damage after receiving phosphate in a 24-hour period has not for sodium phosphates enema products. a pediatric sodium phosphates enema. been demonstrated at this time. Another comment stated that the dosage Reedy and Zwiren (Ref. 20) reported Therefore, the agency will not include a and administration section of products that a 17-month-old child received two greater dosage in a 24-hour period in the containing sodium phosphates should pediatric sodium phosphates enemas as OTC or professional labeling in the final be allowed to contain statements similar a ‘‘bowel prep’’ on the day of surgery monograph for OTC laxative drug to the following proposed warning: ‘‘Do and was successfully resuscitated after products, which will be published in a not exceed recommended dose unless experiencing cardiac arrest during future issue of the Federal Register. directed by a doctor. Serious side effects induction of anesthesia. The authors The agency agrees with the comment may occur from excess dosage.’’ The noted that the child had received that the labeling for sodium phosphates comment indicated that such statements sodium phosphates enemas chronically oral solution should include a warning should be allowed, but do not need to but that a possible electrolyte imbalance not to ingest more than the be included in the final rule. was not suspected, and the child was recommended dose in a 24-hour period. The agency notes that the first not screened for any possible electrolyte Accordingly, the agency is including the comment made an error in its statement problems prior to surgery. Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations 27841

Other authors (Refs. 21, 22, and 23) Sodium Phosphate, Castor Oil, and Standard Enemas in Congenital Megacolon,’’ The have reported acidosis, hypocalcemia, Electrolyte Lavage for Colonoscopy or Journal of the American Medical Association, and hyperphosphatemia that occurred Sigmoidoscopy Preparation,’’ The American 199:574–586, 1967. in adults and children after the use of Journal of Gastroenterology, 88:1218–1223, 25. Grosskopf, I. et al., 1993. ‘‘Hyperphosphatemia and Hypocalcaemia sodium phosphates enema products. 8. Kolts, B. E., ‘‘Response to Drs. Warner Induced by Hypertonic Phosphate Enema— Davis et al. (Ref. 21) state that these and DiPalma,’’ The American Journal of An Experimental Study and Review of the products can cause electrolyte Gastroenterology, 89:1119, 1994. Literature,’’ Human and Experimental imbalances, which can cause severe 9. Cagir, B. et al., ‘‘Hypocalcemia in Toxicology, 10:351–355, 1991. reactions and could result in death, Surgical Critical Care Patients: Measurements 26. Rohack, J. J., B. R. Mehta, and K. when administered in the recommended of Ionized Calcium,’’ Contemporary Surgery, Subramanyam, ‘‘Hyperphosphatemia and doses to individuals with normal renal 45:71–78, 1994. Hypocalcemic Coma Associated with function. 10. Physicians’ Desk Reference, 50th ed., Phosphate Enema,’’ South Medical Journal, The agency is also aware of serious Medical Economics Data Production Co., 78:1241–1242, 1985. electrolyte imbalances occurring in Montvale, NJ, pp. 1002–1004, 1996. 11. Letter from W. E. Gilbertson, FDA, to IV. Summary of Significant Changes individuals who used more than one P. Reichertz, Arent, Fox, Kintner, Plotkin & From the Proposed Rule sodium phosphates enema in a 24-hour Kahn, dated March 1, 1996, coded as period (Refs. 15, 16, 24, 25, and 26). The agency is making the following LET109, Docket No. 78N–036L, Dockets changes based on comments submitted Thus, an electrolyte imbalance can Management Branch. result from an excess dose of either the 12. Wason, S. et al., ‘‘Severe in response to the proposal (59 FR oral solution or the enema dosage form. Hyperphosphatemia, Hypocalcemia, 15139) and other relevant information Because of the serious side effects that Acidosis, and Shock in a 5-Month Old Child that has come to the agency’s attention. can occur from overdosage, the agency Following the Administration of an Adult The agency had proposed to include the considers it important to include Fleet Enema,’’ Annals of Emergency package size limitation and the labeling Medicine, 18:696–700, 1989. information against exceeding the in the final monograph for OTC laxative 13. Oxnard, S. C., J. O’Bell, and W.E. drug products (proposed 21 CFR part recommended dose of sodium Grupe, ‘‘Severe Tetany in an Azotemic Child phosphates drug products in both the 334). However, that final monograph Related to a Sodium Phosphate Enema,’’ has not been completed to date. warnings and directions sections of Pediatrics, 53:105–106, 1974. product labeling. The agency concludes 14. Chesney, R. W., and P. B. Haughton, Therefore, at this time the agency is that this information needs to be ‘‘Tetany Following Phosphate Enemas in including this information in part 201 required, not just voluntarily included Chronic Renal Disease,’’ American Journal of subpart G, Specific Labeling at a manufacturer’s discretion. Diseases of Children, 127:584–586, 1974. Requirements for Specific Drug 15. Honig, P. J., and P. G. Holtzapple, Products. New § 201.307 will be titled III. References ‘‘Hypocalcemic Tetany Following Hypertonic Sodium phosphates; package size The following references are on Phosphate Enemas,’’ Clinical Pediatrics, limitation, warnings, and directions for display in the Dockets Management 14:678–679, 1975. over-the-counter sale. When the laxative 16. Sotos, J. F. et al., ‘‘Hypocalcemic Coma final monograph is complete, it will Branch (address above) and may be seen Following Two Pediatric Phosphate by interested persons between 9 a.m. Enemas,’’ American Academy of Pediatrics, incorporate the requirements in and 4 p.m., Monday through Friday. 60:305–307, 1977. § 201.307. A summary of the changes 1. The United Stated Pharmacopeia 22/ 17. Loughnan, P., and G. C. Mullins, ‘‘Brain made by the agency follows: The National Formulary 17, The United Damage Following a Hypertonic Phosphate 1. The package size limitation of 90 States Pharmacopeial Convention Inc., Enema,’’ American Journal of Diseases of mL (3 oz) for sodium phosphates oral Rockville, MD, pp. 1265–1267, 1989. Children, 131:1032, 1977. solution proposed in § 334.25 appears in 2. The United States Pharmacopeia 23/ The 18. Forman, J., H. J. Baluarte, and A. B. § 201.307(b)(1) and is effective 30 days National Formulary 18, The United States Gruskin, ‘‘Hypokalemia After Hypertonic Pharmacopeial Convention Inc., Rockville, after date of publication of this final rule Phosphate Enemas,’’ Journal of Pediatrics, in the Federal Register. The relabeling MD, pp. 1428–1430, 1994. 94:149–151, 1979. 3. United States Pharmacopeia Dictionary 19. Martin, R. R. et al., ‘‘Fatal Poisoning requirements in § 201.307 are effective of United States Adopted Names and From Sodium Phosphate Enema, Case Report 120 days after date of publication of this International Drug Names, The United States and Experimental Study,’’ Journal of the final rule in the Federal Register. (See Pharmacopeial Convention Inc., Rockville, American Medical Association, 257:2190– comment 2 in section II of this MD, p. 658, 1997. 2192, 1987. document.) 4. Clarkston, W. K. et al., ‘‘A Single Blind Comparison of Serum Electrolytes, Serum 20. Reedy, J. C., and G. T. Zwiren, ‘‘Enema- 2. The agency has revised the warning Phosphorus, Serum Calcium, and Ventricular Induced Hypocalcemia and for oral and rectal dosage forms of Arrhythmias in Outpatients Receiving Hyperphosphatemia Leading to Cardiac sodium phosphates proposed in Nulytely Versus Fleet Phospho-Soda Arrest during Induction of Anesthesia in an § 334.58(c)(2)(iv). The agency is adding Preparation for Colonoscopy: Preliminary Outpatient Surgery Center,’’ Anesthesiology, a new warning for oral sodium 59:578–579, 1983. Results (unpublished study),’’ pp. 1–28, phosphates products, which appears in 1994, OTC vol. 090TFM4, Docket No. 78N– 21. Davis, R. et al., ‘‘Hypocalcemia, Hyperphosphatemia, and Dehydration § 201.307(b)(2)(i) and states: ‘‘Taking 036L, Dockets Management Branch. more than the recommended dose in 24 5. Vanner, S. J. et al., ‘‘A Randomized Following a Single Hypertonic Phosphate Prospective Trial Comparing Oral Sodium Enema,’’ Journal of Pediatrics, 90:484–485, hours can be harmful.’’ (See comment 5 Phosphate with Standard Polyethylene 1977. in section II of this document.) The Glycol-Based Lavage Solution (GoLytely) in 22. Swerdlow, D. B., S. Labow, and F. J. agency is adding a new warning for the Preparation of Patients for Colonoscopy,’’ D’Anna, ‘‘Tetany and Enemas: Report of a rectal sodium phosphates products, The American Journal of Gastroenterology, Case,’’ Diseases of the Colon and the Rectum, which appears in § 201.307(b)(2)(ii) and 85:422–427, 1990. 17:786–787, 1973. states: ‘‘Using more than one enema in 23. Biberstein, M., and B. A. Parker, 6. Warner, B. A., and J. A. DiPalma, ‘‘Oral 24 hours can be harmful.’’ These Sodium Phosphate Catharsis: ‘First Do No Enema-Induced Hyperphosphatemia, The Harm’,’’ The American Journal of American Journal of Medicine, 79:645–646, warnings must appear in boldface type Gastroenterology, 89:1118–1119, 1994. 1985. and must be the first statement in 7. Kolts, B. E. et al., ‘‘A Comparison of the 24. Fonkalsrud, E., and J. Keen, product labeling under the heading Effectiveness and Patient Tolerance of Oral ‘‘Hypernatremic Dehydration Hypertonic ‘‘Warnings.’’ 27842 Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations

3. The agency is adding new information. In addition, the agency is toxicity when consumers use these directions in § 201.307(b)(3)(i) for oral including specific directions that inform products. and rectal sodium phosphates that state: consumers not to take more than the The manufacturer of the only major ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) ‘‘more unless recommended daily dose in a 24-hour trade product containing sodium directed by a doctor. See Warnings.’’ period in § 201.307(b)(3)(ii). (See phosphates oral solution marketed in a (See comment 4 in section II of this comment 3 in section II of this container size larger that 90 mL has document.) These directions must be in document.) already withdrawn that size product boldface type and immediately precede from the market. The agency is not able the dosage information. VI. Analysis of Impacts to identify any other sodium phosphates 4. The agency is including specific No comments were received in oral solution marketed by another directions in § 201.307(b)(3)(ii) that response to the agency’s request for manufacturer in a container exceeding inform consumers not to take more than specific comment on the economic 90 mL. the recommended daily dose in a 24- impact of this rulemaking (59 FR 15139 Regarding relabeling, the agency has hour period. (See comment 3 in section at 15141). FDA has examined the been informed that relabeling costs of II of this document.) impacts of the final rule under the type required by this final rule generally average about $2,000 to $3,000 V. The Agency’s Final Conclusions on Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. per stock keeping unit (SKU) OTC Laxative Drug Products (individual products, packages, and Containing Sodium Phosphates 601–612). Executive Order 12866 directs agencies to assess all costs and benefits sizes). The agency is aware of 3 The agency has determined that there of available regulatory alternatives and, manufacturers that together produce 4 is sufficient evidence to show that an when regulation is necessary, to select SKU’s of oral sodium phosphates drug overdose of sodium phosphates regulatory approaches that maximize products and approximately 125 SKU’s products can cause an electrolyte net benefits (including potential of rectal sodium phosphates drug imbalance. This imbalance can occur if economic, environmental, public health products. There may be a few additional an excess dose of either the sodium and safety, and other advantages; small manufacturers or a few additional phosphates oral solution or the sodium distributive impacts; and equity). Under products in the marketplace that are not phosphates enema were used. This the Regulatory Flexibility Act, if a rule identified in the sources FDA reviewed. electrolyte imbalance can cause severe has a significant economic impact on a Assuming that there are about 130 reactions and result in death. substantial number of small entities, an affected OTC SKU’s in the marketplace, Accordingly, this final rule establishes a agency must analyze regulatory options total one-time costs of relabeling would container size limit for oral sodium that minimize any significant impact of be $260,000 to $390,000. The agency phosphates products and new warning believes that actual cost could be lower the rule on small entities. and direction statements for OTC for several reasons. First, most of the laxative drug product containing Title II of the Unfunded Mandates label changes will be made by private sodium phosphates. To better protect Reform Act (2 U.S.C. 1501 et seq.) label manufacturers that tend to use consumers who use products containing requires that agencies prepare a written simpler and less expensive labeling. these ingredients, the agency concludes statement and economic analysis before Second, the agency is allowing that the container size must be limited proposing any rule that may result in an supplementary labeling (e.g., stick-on to 90 mL (3 oz). In addition, labeling expenditure in any one year by State, labeling) to be used for those products needs to alert consumers not to exceed local, and tribal governments, in the not undergoing a new labeling printing the recommended dose of an oral or aggregate, or by the private sector, of within 120 days. rectal sodium phosphates product in a $100 million (adjusted annually for The final rule would not require any 24-hour period. Therefore, the agency is inflation). The proposed rule that has new reporting and recordkeeping requiring the following warning for oral led to the development of this final rule activities. Therefore, no additional dosage forms of sodium phosphates in was published on March 31, 1994, professional skills are needed. There are § 201.307(b)(2)(i): ‘‘Taking more than before the Unfunded Mandates Reform no other Federal rules that duplicate, the recommended dose in 24 hours can Act was enacted. The agency explains in overlap, or conflict with the final rule. be harmful.’’ The agency is also this final rule that the final rule will not The agency considered but rejected requiring a similar warning for rectal result in an expenditure in any 1 year several container size and labeling dosage forms of sodium phosphates in by State, local, and tribal governments, alternatives: (1) A container size limit of § 201.307(b)(2)(ii): ‘‘Using more than in the aggregate, or by the private sector, 45, 60, or 120 mL; (2) voluntary one enema in 24 hours can be harmful.’’ of $100 million. relabeling; (3) publication of the Furthermore, the agency is requiring The agency believes that this final labeling information in the FDA Drug that the directions for oral and rectal rule is consistent with the principles set Bulletin or professional journals; and (4) sodium phosphates products in out in the Executive Order and in these an exemption from coverage for small § 201.307(b)(3)(i) state: ‘‘Do not’’ (‘‘take’’ two statutes. The purpose of this final entities. The alternate container sizes or ‘‘use’’) ‘‘more unless directed by a rule is to limit the OTC container size were not selected because 90 mL doctor. See Warnings.’’ These additional of one laxative drug product (sodium represents the upper limit of the two statements are intended to refer phosphates oral solution) to not more doses per container and physicians consumers to the warnings when they than 90 mL and to add warning and often prescribe this amount for bowel read the directions for the product. direction statements to the labeling of cleansing prior to surgery and Because of the dire consequences that oral and rectal OTC sodium phosphates diagnostic procedures of the colon. The can occur from an overdose of sodium drug products. This container size agency does not consider voluntary phosphates, the warnings are required limitation and the warning and relabeling or an exemption from to appear in boldface type as the first direction statements concern product coverage acceptable because they do not sentence under the heading toxicity and are intended to help ensure assure that consumers or health ‘‘Warnings.’’ The direction statements the safe and effective use of all OTC professionals will have the most recent are required to appear in boldface type sodium phosphates drug products. needed information for safe and immediately preceding the dosage Potential benefits include reduced effective use of these sodium Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations 27843 phosphates drug products. The agency VII. Paperwork Reduction Act of 1995 occurred because the 240-mL container considers the third alternative useful FDA concludes that the labeling was mistakenly used instead of the 45- and may proceed with such requirements in this document are not mL or 90-mL container. The Food and publications. However, such subject to review by the Office of Drug Administration is limiting the publications do not provide a Management and Budget because they amount of sodium phosphates oral permanent labeling requirement, which do not constitute a ‘‘collection of solution to not more than 90 mL (3 the agency considers necessary for these information’’ under the Paperwork ounces (oz)) per OTC container because products. Reduction Act of 1995 (44 U.S.C. 3501 of the serious health risks associated This final rule may have a significant et seq.). Rather, the labeling statements with the ingestion of larger than economic impact on the manufacturers are a ‘‘public disclosure of information intended doses of this product. Further, of this product, all of which are orginally supplied by the Federal because an overdose of either oral or considered small entities, using the U.S. rectal enema sodium phosphates can government to the recipient for the Small Business Administration cause an electrolyte imbalance, purpose of disclosure to the public’’ (5 designations for this industry (750 additional warning and direction CFR 1320.3(c)(2)). employees). The agency believes that statements are required for the safe use any other unidentified manufacturer of VIII. Environmental Impact of any OTC laxative drug product these products may also be a small The agency has determined under 21 containing sodium phosphates. entity. These manufacturers will need to CFR 25.31(c) that this action is of a type (b) Any OTC drug product for laxative change the information panel of each that does not individually or or bowel cleansing use containing affected sodium phosphates SKU. cumulatively have a significant effect on sodium phosphates as an active ingredient when marketed as described Among the steps the agency is taking to the human environment. Therefore, minimize the impact on these small in paragraph (a) of this section is neither an environmental assessment entities are: (1) To provide 120 days for misbranded within the meaning of nor an environmental impact statement implementation, as one comment section 502 of the Federal Food, Drug, is required. requested, to enable entities to use up and Cosmetic Act unless packaged and some existing labeling stock, and (2) to List of Subjects in 21 CFR Part 201 labeled as follows: provide for the use of supplementary Drugs, Labeling, Reporting and (1) Package size limitation for sodium labeling (e.g., stick-on labeling) if recordkeeping requirements. phosphates oral solution: Container necessary. The agency believes that Therefore, under the Federal Food, shall not contain more than 90 mL (3 these actions should help reduce the Drug, and Cosmetic Act, and under oz). relabeling cost for small entities. authority delegated to the Commissioner (2) Warnings. The following sentences The agency considered a longer of Food and Drugs, 21 CFR part 201 is shall appear in boldface type as the first implementation period. The agency amended as follows: statement under the heading proposed a 30-day effective date, ‘‘Warnings.’’ considered extending this to 60 days, PART 201ÐLABELING (i) Oral dosage forms. ‘‘Taking more and in response to public comment has than the recommended dose in 24 hours extended the effective date to 120 days 1. The authority citation for 21 CFR can be harmful.’’ to reduce the economic burden on small part 201 continues to read as follows: (ii) Rectal enema dosage forms. entities. The agency considered but Authority: 21 U.S.C. 321, 331, 351, 352, ‘‘Using more than one enema in 24 rejected a longer effective date because 353, 355, 356, 357, 358, 360, 360b, 360gg– hours can be harmful.’’ it would not assure that consumers have 360ss, 371, 374, 379e; 42 U.S.C. 216, 241, (3) Directions—(i) The labeling of all the most recent needed information for 262, 264. orally or rectally administered OTC safe and effective use of OTC sodium 2. Section 201.307 is added to subpart drug products containing sodium phosphates drug products at the earliest G to read as follows: phosphates shall contain the following possible time. The agency concludes directions in boldface type immediately that the overriding safety considerations § 201.307 Sodium phosphates; package preceding the dosage information: ‘‘Do warrant a 120-day implementation size limitation, warnings, and directions for not’’ (‘‘take’’ or ‘‘use’’) ‘‘more unless period. over-the-counter sale. directed by a doctor. See Warnings.’’ The analysis shows that this final rule (a) Reports in the medical literature (ii) For products containing dibasic is not economically significant under and data accumulated by the Food and sodium phosphate/monobasic sodium Executive Order 12866 and that the Drug Administration indicate that phosphate identified in § 334.16(d) agency has undertaken important steps multiple container sizes of sodium marketed as a solution. Adults and to reduce the burden to small entities. phosphates oral solution available in the children 12 years of age and over: Oral Nevertheless, some entities, especially marketplace have caused consumer dosage is dibasic sodium phosphate those private label manufacturers that confusion and appear to have been 3.42 to 7.56 grams (g) and monobasic provide labeling for a number of the involved in several consumer deaths. sodium phosphate 9.1 to 20.2 g (20 to affected products, may incur significant Sodium phosphates oral solution has 45 mL dibasic sodium phosphate/ impacts. Thus, this economic analysis, been marketed in 45-milliliter (mL), 90- monobasic sodium phosphate oral together with other relevant sections of mL, and 240-mL container sizes. The solution) as a single daily dose. ‘‘Do not this document, serves as the agency’s 45-mL and 90-mL container sizes of take more than 45 mL (9 teaspoonfuls or final regulatory flexibility analysis, as sodium phosphates oral solution are 3 tablespoonfuls) in a 24-hour period.’’ required under the Regulatory often recommended and prescribed by Children 10 and 11 years of age: Oral Flexibility Act. Finally, this analysis physicians for bowel cleansing prior to dosage is dibasic sodium phosphate shows that the Unfunded Mandates Act surgery and diagnostic procedures of the 1.71 to 3.78 g and monobasic sodium does not apply to the final rule because colon. Sodium phosphates oral solution phosphate 4.5 to 10.1 g (10 to 20 mL it would not result in an expenditure in (adult dose 20 mL to 45 mL) is also used dibasic sodium phosphate/monobasic any one year by State, local, and tribal as an over-the-counter (OTC) laxative sodium phosphate oral solution) as a governments, in the aggregate, or by the for the relief of occasional constipation. single daily dose. ‘‘Do not take more private sector, of $100 million. Accidental overdosing and deaths have than 20 mL (4 teaspoonfuls) in a 24- 27844 Federal Register / Vol. 63, No. 98 / Thursday, May 21, 1998 / Rules and Regulations hour period.’’ Children 5 to 9 years of List of Subjects in 21 CFR Part 510 FOR FURTHER INFORMATION CONTACT: age: Oral dosage is dibasic sodium Thomas J. McKay, Center for Veterinary Administrative practice and phosphate 0.86 to 1.89 g and monobasic Medicine (HFV–102), Food and Drug procedure, Animal drugs, Labeling, sodium phosphate 2.2 to 5.05 g (5 to 10 Administration, 7500 Standish Pl., Reporting and recordkeeping mL dibasic sodium phosphate/ Rockville, MD 20855, 301–827–0213. requirements. monobasic sodium phosphate oral Therefore, under the Federal Food, SUPPLEMENTARY INFORMATION: Hoffmann- solution) as a single daily dose. ‘‘Do not La Roche, Inc., Nutley, NJ 07110, has take more than 10 mL (2 teaspoonfuls) Drug, and Cosmetic Act and under authority delegated to the Commissioner informed FDA that it has transferred the in a 24-hour period.’’ Children under 5 ownership of and all rights and interests years of age: ask a doctor. of Food and Drugs and redelegated to the Center for Veterinary Medicine, 21 in approved NADA’s and ANADA’s to (c) After June 22, 1998, for package CFR part 510 is amended as follows: Roche Vitamins, Inc., 45 Waterview size limitation and September 18, 1998, Blvd., Parsippany, NJ 07054–1298. for labeling in accord with paragraph (b) PART 510ÐNEW ANIMAL DRUGS Accordingly, the agency is amending of this section, any such OTC drug the regulations in 21 CFR parts 510 and product initially introduced or initially 1. The authority citation for 21 CFR 558 to reflect the change of sponsor. The delivered for introduction into interstate part 510 continues to read as follows: agency is also amending the regulations commerce, or any such drug product Authority: 21 U.S.C. 321, 331, 351, 352, in § 510.600(c)(1) and (c)(2) by removing that is repackaged or relabeled after 353, 360b, 371, 379e. Hoffmann-La Roche, Inc., because the these dates regardless of the date the sponsor no longer sponsors any product was manufactured, initially § 510.600 [Amended] approved new animal drugs, and by alphabetically adding an entry for Roche introduced, or initially delivered for 2. Section 510.600 Names, addresses, Vitamins, Inc. introduction into interstate commerce, and drug labeler codes of sponsors of that is not in compliance with this approved applications is amended in List of Subjects section is subject to regulatory action. the table in paragraph (c)(1) by 21 CFR Part 510 Dated: April 28, 1998. removing the entry for ‘‘Protiva, A Unit William K. Hubbard, of Monsanto Co.’’ and by alphabetically Administrative practice and Associate Commissioner for Policy adding a new entry for ‘‘Monsanto Co., procedure, Animal drugs, Labeling, Coordination. 800 North Lindbergh Blvd., St. Louis, Reporting and recordkeeping [FR Doc. 98–12053 Filed 5–20–98; 8:45 am] MO 63167’’ and in the table in requirements. paragraph (c)(2) in the entry for BILLING CODE 4160±01±F 21 CFR Part 558 ‘‘059945’’ by removing the sponsor name ‘‘Protiva, A Division of Monsanto Animal drugs, Animal feeds. DEPARTMENT OF HEALTH AND Co.’’ and adding in its place ‘‘Monsanto Therefore, under the Federal Food, HUMAN SERVICES Co.’’ Drug, and Cosmetic Act and under Dated: May 8, 1998. authority delegated to the Commissioner Food and Drug Administration Andrew J. Beaulieu, of Food and Drugs and redelegated to the Center for Veterinary Medicine, 21 Acting Director, Office of New Animal Drug 21 CFR Part 510 CFR parts 510 and 558 are amended as Evaluation, Center for Veterinary Medicine. follows: Animal Drugs, Feeds, and Related [FR Doc. 98–13162 Filed 5–20–98; 8:45 am] Products; Change of Sponsor Name BILLING CODE 4160±01±F PART 510ÐNEW ANIMAL DRUGS

AGENCY: Food and Drug Administration, 1. The authority citation for 21 CFR HHS. DEPARTMENT OF HEALTH AND part 510 continues to read as follows: HUMAN SERVICES ACTION: Final rule. Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e. Food and Drug Administration SUMMARY: The Food and Drug § 510.600 Names, addresses, and drug Administration (FDA) is amending the 21 CFR Parts 510 and 558 labeler codes of sponsors of approved applications. animal drug regulations to reflect the Animal Drugs, Feeds, and Related 2. Section 510.600 is amended in the change of sponsor name from Protiva, a Products; Change of Sponsor unit of Monsanto, to Monsanto Co. table in paragraph (c)(1) by removing AGENCY: the entry for ‘‘Hoffmann-La Roche, EFFECTIVE DATE: May 21, 1998. Food and Drug Administration, HHS. Inc.,’’ and by alphabetically adding an FOR FURTHER INFORMATION CONTACT: entry for ‘‘Roche Vitamins, Inc.,’’ and in ACTION: Final rule. Thomas J. McKay, Center for Veterinary the table in paragraph (c)(2) by removing the entry for ‘‘000004’’ and by Medicine (HFV–102), Food and Drug SUMMARY: The Food and Drug Administration, 7500 Standish Pl., Administration (FDA) is amending the numerically adding an entry for Rockville, MD 20855, 301–827–0213. animal drug regulations to reflect a ‘‘063238’’ to read as follows: SUPPLEMENTARY INFORMATION: Protiva, a change of sponsor for 96 new animal § 510.600 Names, addresses, and drug unit of Monsanto has informed FDA of drug applications (NADA’s) and 4 labeler codes of sponsors of approved a change of sponsor name to Monsanto abbreviated animal drug applications applications. Co. Accordingly, FDA is amending 21 (ANADA’s) from Hoffmann-La Roche, * * * * * CFR 510.600(c)(1) and (c)(2) to reflect Inc., to Roche Vitamins, Inc. (c) * * * the change of sponsor name. EFFECTIVE DATE: May 21, 1998. (1) * * *