Labeling of Diphenhydramine-Containing Drug Products for Over- the-Counter Human Use

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 336, 338, 341, and 348

[Docket No. 97N-0128]

RIN 0910-AA01

Labeling of Diphenhydramine-Containing Drug Products for Over-

the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the tentative final monograph for over-the-counter (OTC) external

analgesic drug products, and the final monographs for oral OTC

diphenhydramine drug products for antiemetic, antihistamine,

antitussive, and nighttime sleep-aid indications. The amendment adds

warning statements concerning diphenhydramine toxicity. The proposed

warnings advise consumers not to use topical products containing

diphenhydramine on chicken pox, poison ivy, sunburn, large areas of the

body, blistered or oozing skin, more often than directed, or with any

other product containing diphenhydramine, even one taken by mouth, and

not to use oral OTC diphenhydramine products with any other product

containing diphenhydramine including products used topically. This

proposal is part of the ongoing review of OTC drug products conducted

by FDA.

DATES: Submit written comments by November 28, 1997. FDA is proposing

that any final rule that may issue based on this proposal become

effective 12 months after the date of its publication in the Federal

Register.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Nahid Mokhtari-Rejali, Center for Drug

Evaluation and Research (HFD-560), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

Diphenhydramine hydrochloride is proposed for inclusion in the

monograph for OTC external analgesic drug products for topical use as

an antihistamine external analgesic.

[[Page 45768]]

Diphenhydramine hydrochloride is also included in the OTC drug

monograph for oral use as an antiemetic (21 CFR part 336). Both

diphenhydramine citrate and diphenhydramine hydrochloride are included

in OTC drug monographs for oral use as a nighttime sleep-aid (21 CFR

part 338), an antihistamine, or an antitussive (21 CFR part 341). The

various OTC advisory review panels that reviewed diphenhydramine for

these different uses as part of the OTC drug review did not consider

interactions that may occur when a person takes oral diphenhydramine

and applies diphenhydramine topically.

In the Federal Register of December 4, 1979 (44 FR 69768), the

Advisory Review Panel on OTC Topical Analgesic, Antirheumatic, Otic,

Burn, and Sunburn Prevention and Treatment Drug products (the Panel)

evaluated the safety and effectiveness of diphenhydramine hydrochloride

as an antihistamine external analgesic. The Panel acknowledged that

diphenhydramine is absorbed through damaged skin and gains access to

the blood stream. However, the Panel did not consider systemic toxicity

from topical application to be of major importance because of its low

degree of toxicity when used orally or parenterally. The Panel was

unaware of any instance of systemic toxicity reported from topical use

of diphenhydramine. The Panel concluded that the drug was safe at 1- to

2-percent concentrations for the temporary relief of pain and itching

due to minor burns, sunburn, minor cuts, abrasions, insect bites, and

minor skin irritations. The only warning the Panel recommended was not

to use for longer than 7 days except under the advice and supervision

of a physician (44 FR 69768 at 69809).

The agency concurred with the Panel's recommendations in the

tentative final monograph for OTC external analgesic drug products,

published in the Federal Register of February 8, 1983 (48 FR 5852). The

agency did not change the Panel's recommended warnings for

diphenhydramine, or add any other warnings.

II. Developments After Publication of the External Analgesic

Tentative Final Monograph

Since publication of the external analgesic tentative final

monograph, the agency has become aware of reports of adverse events

(toxic psychosis), especially in children, when diphenhydramine was

used topically for relief of pruritus due to chicken pox, poison ivy,

and sunburn. Some reports mentioned the concurrent use of topical

diphenhydramine with oral diphenhydramine drug products to relieve the

itch and rash associated with chicken pox. Chicken pox is not a

monograph indication for topical or oral diphenhydramine products.

A. Early Case Reports to FDA

The agency has reviewed case reports of toxic psychosis reported to

its Spontaneous Reporting System for the period from 1979 to 1989 (Ref.

1).

In 1979, a 6-year-old boy developed chicken pox and was treated

with baking soda baths (8 ounce (oz)/tub) every 2 hours followed by

topical application of a lotion containing 1 percent diphenhydramine

and calamine every 2 hours. Twelve hours later he developed unusual

behavior (talking to imaginary people, playing with imaginary toys, did

not recognize parents). On the third day, a doctor saw the child and

prescribed diphenhydramine elixir every 4 hours. After 2 doses, the boy

became agitated and his strange ideas became worse. He was hospitalized

with hallucinations, bizarre inappropriate behavior, and disorientation

to time and place. He was afebrile. His pupils were dilated and his

face was flushed. Diphenhydramine in calamine and diphenhydramine

elixir were suspected of causing the toxic psychosis. The child was

given no medication and the following morning he was fully alert and

his behavior was normal, without hallucinations or delusions.

In 1980, a physician reported that diphenhydramine from a 1 percent

diphenhydramine-calamine lotion was absorbed in high concentrations in

two patients who were afebrile in the late stages of chicken pox. The

first patient had diphenhydramine lotion painted on the body and sealed

with a dryer by his mother. The patient developed hallucinations and

delirium. A second patient who had the same lotion applied but not

sealed also developed hallucinations. The physician noted that

hallucinations and delirium would not be expected in the late stages of

this disease.

In 1987, an 8-year-old child was admitted to the hospital for

severe psychosis, urinary retention, ataxia, bizarre posturing, and

dilated pupils. During the 12 hours before admission, 1 percent

diphenhydramine-calamine lotion was applied three different times on

the child from head to toe for severe poison ivy contact dermatitis. A

toxic drug screen was negative for diphenhydramine but revealed traces

of benzodiazepine which the child might have ingested. No other

medication was given. The diphenhydramine lotion was removed and the

child recovered fully.

In 1989, a pharmacist reported that his 6-year-old son experienced

toxic psychoses (hyperactive, jittery, disoriented with visual

hallucinations) within 24 hours of application of 1 percent

diphenhydramine-calamine lotion to chicken pox lesions. Diphenhydramine

elixir was given 2 days before and on the day of the topical

application. The child was hospitalized, treated with activated

charcoal, and recovered completely within 24 hours, with no further

problems.

B. Early Pediatric Literature

Patranella (Ref. 2) reported an incident where a 4-year-old boy

became toxic after topical application of 3 oz of 1 percent

diphenhydramine-calamine lotion to chicken pox rash. The child was

admitted to the hospital because of increasing hyperactivity, irregular

eye movements, hallucinations, and intermittently failing to recognize

his parents. The rash developed the day before admission, 16 days after

exposure to varicella. The child's pupils were 4 millimeters in

diameter and reacted sluggishly to light. He was awake, disoriented to

person and place, combative, ataxic, and displayed tongue rolling. A

urine drug screen revealed the presence of diphenhydramine. The lotion

was washed from his skin with water and his mental status returned to

normal within 6 to 8 hours. The report noted that diphenhydramine is a

histamine (H1) receptor blocker which can cause central

nervous system excitation or sedation. The fatal dose in adults is 20

to 40 milligrams/kilogram (mg/kg). The 4-year-old boy received 50 mg/kg

topically over a 6-hour period.

Filloux (Ref. 3) described a 9-year-old boy with chicken pox who

had 1 percent diphenhydramine-calamine lotion applied liberally from

head to toe, a total of 12 oz in 48 hours, for intense pruritus.

Diphenhydramine toxicity resulted with organic psychosis masquerading

as varicella encephalitis, a serious neurologic complication of

varicella zoster (chicken pox) disease that can result in permanent

neurologic sequelae or death. On admission to the emergency room, the

boy was markedly agitated, frightened, disoriented, completely

confused, having frequent visual and auditory hallucinations, and would

assume bizarre postures. Pupils were dilated but reactive. Laboratory

results were within normal limits. The serum toxic screen showed a

diphenhydramine level of 1.4 micrograms per milliliter (g/mL),

which exceeded the therapeutic level of 0.3 g/mL. No further

diphenhydramine

[[Page 45769]]

lotion was applied. Although agitated and hallucinating through the

night, the following morning he was calmer, but still confused. His

diphenhydramine level had dropped to 0.7 g/mL. He was lucid by

noon and by 4 p.m. his diphenhydramine level was 0.6 g/mL. He

was discharged from the hospital with a normal mental status. Ample

evidence in this patient confirmed that transdermal absorption of

diphenhydramine resulted in intoxication and organic psychosis. The

report advised that appropriate caution was warranted when treating

pruritus with topical antihistamine preparations, particularly when

substantial epidermal breakdown exists.

Tomlinson, Helfaer, and Wiedermann (Ref. 4) described a case of

diphenhydramine toxicity mimicking varicella encephalitis. Physical

examination disclosed evidence of diphenhydramine toxicity related to

systemic absorption of a topical preparation. The patient, a 5-year-old

girl, developed chicken pox rash 4 days before admission to the

hospital. Her mother had applied 1 percent diphenhydramine-calamine

lotion repeatedly over most of the child's body during this 4-day-

period, but gave no other medications. The day before admission the

child appeared agitated, did not sleep, had an unsteady gait, and had

trembling of the extremities. Later, she developed visual

hallucinations and her speech became unintelligible. Upon admission to

the hospital, she was disoriented, agitated, and grasping at imaginary

objects in the air. Neurologic examination revealed dilated pupils,

flushed face, and ataxia. A urine toxicity screen was positive only for

diphenhydramine. The child's status improved quickly after the

diphenhydramine lotion was removed. No other therapy was given and she

was discharged on the fourth day. A followup examination done 2 weeks

later was normal.

Although initially believed to have varicella encephalitis, the

child's symptoms (ataxia, hallucinations, mydriasis, and flushing of

the face) were more suggestive of an anticholinergic reaction. Tests

confirmed diphenhydramine toxicity rather than varicella encephalitis.

The report concurred with one manufacturer's recommendations that

diphenhydramine not be used in skin disorders, such as varicella, where

extensive systemic absorption of topical preparations may occur. The

report suggested that families of children with chicken pox be warned

to be cautious in the use of this drug product.

Schunk and Svendsen (Ref. 5) reported on three children (ages 4, 5,

and 7) with chicken pox who developed toxic encephalopathy from having

been treated with both oral and topical diphenhydramine. All displayed

some of the symptoms common to diphenhydramine toxicity: Dilated

pupils, flushed face, agitation, confusion, hallucinations, and ataxic

gait. The plasma diphenhydramine level was 1.5 g/mL in the 4-

year-old and 0.96 g/mL in the 5-year-old. After discontinuing

the diphenhydramine, all children displayed normal mental status.

This report advised that physicians should be alerted to the

possibility of diphenhydramine toxicity when confronted with a child

with varicella and acute mental status changes. Further, both families

and physicians should be advised against combined use of topical and

oral diphenhydramine-containing preparations.

Woodward and Baldassano (Ref. 6) described a case of

diphenhydramine intoxication from the combined effects of oral

diphenhydramine elixir and topical diphenhydramine-calamine lotion in a

5-year-old boy who developed chicken pox 3 days before being taken to

the emergency room. He had been treated with 6 or 7 teaspoons of oral

diphenhydramine (12.5 mg/5 mL) for a total dosage of 75 to 87 mg (over

36 hours). His mother also had applied 1 percent diphenhydramine-

calamine lotion liberally over his body in a 12-hour period, 24 hours

prior to presentation in the emergency department. The boy's behavior

was bizarre; he was talking to and seeing objects and people that were

not present. The boy had the classic symptoms of diphenhydramine

toxicity, including hallucinations, tachycardia, and dilated pupils. A

toxic screen showed both acetaminophen and diphenhydramine (1.94/

g/L approximately 14 hours after the last oral dose). All

diphenhydramine was discontinued, and the child returned to normal the

next day. Varicella encephalitis was ruled out. The report stated that

children more often show excitation with overdosage of antihistamines

than the usual sedative effect seen in adults.

The article further stated that data on percutaneous absorption of

diphenhydramine are limited. The recommended oral dose is 5 mg/kg/24

hours and three to four applications of topical diphenhydramine lotion

per day. The child had a total of 3.6 mg/kg/36 hours, or less, of oral

diphenhydramine, less than half the daily recommended dosage, and a

larger amount of lotion over a 12-hour period. Therefore, absorption of

the lotion appears to have been a primary factor in the adverse

reaction. The report noted that toxicity from oral use is more common

than toxicity from topical use of diphenhydramine. Fatalities have been

reported in both children and adults from oral overdosage. However, no

deaths have been reported from topical diphenhydramine use alone. The

report advised that physicians and patients need to be aware of this

potential toxicity.

C. More Recent Case Reports

Between 1987 and 1990, a major manufacturer of OTC diphenhydramine

drug products received four adverse event reports that described toxic

psychoses in seven children (Ref. 7). Apparently the drug products were

being misused, contrary to labeling, and were being applied to large

areas of the body where there was broken skin, possibly causing

increased systemic absorption. Based on these seven cases, the

manufacturer voluntarily revised the label warnings for its topical

products containing diphenhydramine. In 1989, the manufacturer added to

the following products a warning not to use on chicken pox and measles

unless supervised by a doctor: A cream and lotion product containing 1

percent diphenhydramine and 8 percent calamine, and a cream and spray

product containing 1 percent diphenhydramine and 0.1 percent zinc

acetate. In 1990, the manufacturer added to these products a second

warning not to use any other drugs containing diphenhydramine while

using the topical products. This warning was added based on reports

that the topical diphenhydramine drug products were being used with

oral diphenhydramine drug products to relieve the itch and rash

associated with chicken pox and measles, possibly resulting in toxic

serum diphenhydramine levels. In April 1993, the manufacturer

reformulated its lotion and cream products containing 1 percent

diphenhydramine and 8 percent calamine to replace the diphenhydramine

with 1 percent pramoxine hydrochloride.

Summaries of the adverse event reports received by the manufacturer

follow:

The first report involved a 7-year-old boy who developed chicken

pox. Oral hydroxyzine hydrochloride (one dose at 6:30 p.m.) was

prescribed. The child's mother applied 5 to 10 mL of 1 percent

diphenhydramine-calamine lotion three times to the child's abdomen and

chest between 7:45 and 11:30 p.m. Around 12

[[Page 45770]]

a.m., the child became confused, irritable, and began hallucinating.

When hospitalized, his diphenhydramine level at 5:40 a.m. was 73

nanograms per mL (ng/mL) (the normal level is 25 to 40 ng/mL). The

diphenhydramine-calamine lotion was removed from the skin and the child

recovered uneventfully the next day.

The second report involved four children, ages 4 to 6 years, who

developed chicken pox. Typically, the mothers applied 1 percent

diphenhydramine-calamine lotion over an extensive area of the body

three to four times daily. In one case, the child was concurrently

receiving diphenhydramine syrup. In all cases, within 24 to 48 hours,

the children became irritable, delirious, and began hallucinating. The

children were treated in an emergency room by washing the

diphenhydramine lotion from their bodies, and they responded within 24

to 36 hours.

The third report concerned a 9-year-old boy with a mild sunburn

without broken or blistered skin. An hour after his mother liberally

applied one-half of a 45-gram tube of 1 percent diphenhydramine-

calamine cream to the boy's trunk and limbs, he developed increased

tiredness and became confused and disoriented. He convulsed, with

widespread muscular twitching and ``rolling of the eyes'' 1\1/2\ to 2

hours after the cream had been applied. He was taken to the hospital

and a chemical toxicology screen revealed a diphenhydramine level of 60

ng/mL. The child was treated with activated charcoal and intravenous

fluids. Approximately 32 hours later, the diphenhydramine level was 16

ng/mL; the child recovered uneventfully and was discharged the

following day.

The fourth report described an 8-year-old boy with a history of

allergies and asthma who developed extensive chicken pox. One percent

diphenhydramine-calamine lotion was applied all over the body every 4

to 5 hours for approximately 48 hours. The child complained of blurred

vision and ``not being able to see clearly'' on the second day after

``breaking out.'' He received acetaminophen every 4 to 5 hours for

fever. About 2 to 3 a.m., the child awoke with hallucinations of flying

insects. A dose of acetaminophen and a teaspoon of diphenhydramine

elixir were given, and additional diphenhydramine-calamine lotion was

applied. Afterwards, the boy's body was twitching, he was restless and

unable to sit still or sleep. On the advice of the local emergency

room's personnel, the child was placed in a cool tub of water to lower

his temperature (103 to 104 deg.F). Although his temperature was

reduced, the boy continued to hallucinate. After another application of

diphenhydramine-calamine lotion, the child was taken to the hospital

around 7 a.m., still hallucinating. Neurological tests and a test for

Reye's syndrome were negative, and the child was sent home. Another

dose of diphenhydramine-calamine lotion was applied at 11 a.m. and

after 1 to 2 hours the child began to bump into a hallway wall and was

unable to sit still. The last dose of diphenhydramine lotion was

applied mid-afternoon. A few hours later, the boy fell asleep for 4

hours, awoke vomiting, and had difficulty breathing. After these

problems subsided, the child recovered uneventfully.

In the last 6 years, FDA has received several additional reports of

toxic psychoses as a result of topical application of diphenhydramine.

One doctor reported two cases in children who had symptoms of delirium

from absorption of diphenhydramine from a 1 percent diphenhydramine-

calamine product applied to their bodies (Ref. 8). One child had a

blood level of 0.31 g/mL while the other child's blood level

was drawn much later and was not indicative of a toxic level. The

doctor expressed concern about the potential side effects of the

diphenhydramine in this product.

Chan and Wallender (Ref. 9) reported three cases of diphenhydramine

toxicity. Two of the cases were included in earlier articles discussed

previously. The third case described a 2-year-old boy who developed

chicken pox lesions over his body. He was given an unknown amount of

diphenhydramine elixir every 3 to 4 hours, and a 1 percent

diphenhydramine-calamine in a lotion and/or spray was applied topically

to most of his body surface. The child became increasingly irritable

and displayed inappropriate behavior. The parents contacted the

emergency room and were instructed to bathe the child to remove the

diphenhydramine lotion. However, the child continued to have

inappropriate behavior and visual hallucinations, and was brought to

the emergency room 4 hours later. Vital signs were temperature 37.1

deg.C (rectally), heart rate 124 beats per minute, and respiration 36

breaths per minute. Chicken pox lesions covered his body and, although

he had brief periods of inappropriate behavior, he was able to follow

simple commands. The serum diphenhydramine concentration was 1.5

g/mL. Based on laboratory reports, diphenhydramine

concentrations greater than 0.1 g/mL are potentially toxic.

After 2 hours of observation, the boy was dismissed. He was alert and

playful without evidence of toxicity during a follow-up examination

later that morning.

The report noted that the topical diphenhydramine products used in

treating the patients discussed in the article had a label warning

against use in chicken pox unless supervised by a physician. According

to the authors, cases described in the article demonstrated three

important points. First, absorption of topically applied

diphenhydramine in patients with chicken pox and possibly other skin

disorders with extensive disruption of the skin barrier can occur,

resulting in serious systemic toxicity. Second, the use of topically

applied diphenhydramine products in this patient population should be

discouraged. Finally, pharmacists should educate the public as well as

health professionals regarding the potential toxicity of these easily

accessible diphenhydramine-containing nonprescription medications.

McGann et al. (Ref. 10) reported a case of a 19-month-old girl who

developed chicken pox 5 days before being brought to the clinic. The

girl had been treated with acetaminophen for fever, colloidal oatmeal

baths, 1 percent diphenhydramine-calamine lotion applied to her entire

body three or four times a day, and syrup given in varying doses

totaling approximately 50 mg of diphenhydramine. Two hours later, the

child began behaving strangely and rolling her eyes back into her head.

When brought to the clinic, the child was awake but did not

interact with the examiner. She was moderately agitated and frightened;

would not respond to commands; had a wide-eyed stare; had widely

dilated pupils that were sluggishly reactive to light; occasionally

made grimacing, tongue-chewing, and lip-smacking motions; staggered

when walking; and retained urine. Her serum diphenhydramine level was

1,948 ng/mL. The girl was bathed to remove the diphenhydramine, then

admitted to the hospital for hydration, cardiac monitoring, bladder

catheterization for urine retention, and observation. After 48 hours,

she had returned to normal and was discharged from the hospital.

The report cautioned parents to refrain from using topical

diphenhydramine to avoid a serious life-threatening drug toxicity, and

noted that the drug label specifically warns against use for chicken

pox and measles, except under the supervision of a physician. The

agency notes that the labeling directions proposed in Sec. 348.50(d) of

the tentative final monograph for OTC external analgesic

[[Page 45771]]

drug products (48 FR 5852 at 5869) state that a doctor should be

consulted for children under 2 years of age. The report did not

indicate whether a doctor had prescribed the drug.

III. The Agency's Tentative Conclusions and Proposal

The case reports described a number of adverse events resulting

from topical application of diphenhydramine to large areas of the body,

often where there was broken skin and, in some cases, concurrent use of

topical and oral diphenhydramine products. The diphenhydramine products

were used to relieve pain and itching due to chicken pox (most cases),

poison ivy (1 case), and sunburn (1 case). The age range of the

patients with reactions was 19 months to 9 years. The symptoms

determined to be most suggestive of diphenhydramine toxicity included

dilated pupils, flushed face, hallucinations, ataxic gait, and urinary

retention. As the Panel noted (44 FR 69768 at 69809), diphenhydramine

is absorbed through damaged skin, and the case reports confirmed that

transdermal absorption occurs. In some cases, high serum concentrations

confirmed diphenhydramine toxicity. Symptoms gradually disappeared when

diphenhydramine was removed from the body by bathing and oral

administration of diphenhydramine was discontinued. Most patients

returned to normal in about 48 hours after the drug was withdrawn. No

deaths have been reported from topical diphenhydramine use alone.

The authors of many of these reports have indicated the need to

inform health professionals and consumers about the situations when

topical diphenhydramine should not be used, especially in conjunction

with oral diphenhydramine. This is especially true in patients with

chicken pox and possibly other skin disorders with extensive disruption

of the skin barrier, which can result in serious systemic toxicity if

absorption of diphenhydramine occurs. As noted in section II.C. of this

document, a major manufacturer of OTC diphenhydramine drug products

voluntarily added warning information to the labeling of its topical

products.

The agency believes there is underreporting of adverse reactions

for topical diphenhydramine drug products. There is currently no

adverse event reporting requirement for topical diphenhydramine

products included in an OTC drug monograph. In addition, the agency is

concerned that consumers, primarily parents, may use these topical

products casually because they consider them to be innocuous. Because

the exact extent of the problem is not known, and there is a

potentially large exposure of the general population to this

ingredient, the agency has determined that additional warnings are

needed to avoid the possibility of serious adverse reactions. A

sufficient number of significant serious neuropsychiatric events have

already occurred (especially in children) to propose a change in the

labeled warnings for both topical and oral diphenhydramine products. In

this document, the agency is proposing to require the following

additional warning for topical products containing diphenhydramine:

``Do Not Use'' (these three words in bold print) ``on chicken pox,

poison ivy, sunburn, large areas of the body, broken, blistered, or

oozing skin, more often than directed, or with any other product

containing diphenhydramine, even one taken by mouth.''

The agency notes that one manufacturer includes ``not to use on

measles'' in the warning that it voluntarily added to its topical

diphenhydramine products. However, because none of the case reports

were associated with measles lesions, the agency has not specifically

listed measles in the warning. The agency invites interested persons to

submit any available information related to any adverse events

associated with the topical application of diphenhydramine to measles.

Manufacturers may use bullet points or other identifying marks to

emphasize the subparts of this warning. The format of this warning

might look something like the following:

Do Not Use (these words in bold print):

on chicken pox, poison ivy, sunburn

on large areas of the body

on broken, blistered, or oozing skin

more often than directed

with any other product containing diphenhydramine, even

one taken by mouth

The agency is proposing this warning in new Sec. 348.50(c)(10)

under the heading For products containing diphenhydramine hydrochloride

identified in Sec. 348.10(c)(1). For these products, this warning shall

be the first statement under the heading ``Warnings:''

In addition, in Secs. 336.50, 338.50, 341.72, and 341.74 the agency

is proposing an additional warning for oral drug products that contain

diphenhydramine. The warning states: ``Do Not Use'' (these three words

in bold print) ``with any other product containing diphenhydramine,

including one applied topically.'' The agency believes that this

warning statement will help reduce the toxicity that may occur from the

inadvertent concurrent use of several products containing

diphenhydramine. The agency points out that its recent final rule/

enforcement policy that provides for diphenhydramine citrate or

diphenhydramine hydrochloride to be labeled for concurrent

antihistamine and antitussive use should also help reduce the toxicity

that may occur from the concurrent administration of more than one oral

product containing diphenhydramine. (See the Federal Register of April

9, 1996 (61 FR 15700).)

Manufacturers of OTC topical and oral diphenhydramine drug products

are encouraged to implement this labeling addition voluntarily as soon

as possible after publication of this proposal, subject to the

possibility that FDA may change the wording of the warning statement as

a result of comments filed in response to this proposal. Because FDA is

encouraging the voluntary use of the proposed additional warning

statement at this time, the agency advises that manufacturers will be

given ample time after publication of a final rule to use up any

labeling voluntarily implemented in conformance with this proposal.

IV. References

The following references have 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.

(1) Drug Experience Reports No. 801101-034-00101,

80051000100501, 8706110020071, 89081500100012, 89081500100011, OTC

Vol. 06DTFM, Docket No. 78N-0301, Dockets Management Branch.

(2) Patranella, P., ``Diphenhydramine Toxicity Due to Topical

Application of Caladryl,'' Clinical Pediatrics, 3:163, 1986.

(3) Filloux, F., ``Toxic Encephalopathy Caused by Topically

Applied Diphenhydramine,'' The Journal of Pediatrics, 108:1018-1020,

1986.

(4) Tomlinson, G., M. Helfaer, and B. Wiedermann,

``Diphenhydramine Toxicity Mimicking Varicella Encephalitis,'' The

Pediatric Infectious Disease Journal, 6:220-221, 1987.

(5) Schunk, J. E., and D. Svendsen, ``Diphenhydramine Toxicity

from Combined Oral and Topical Use,'' The Pediatric Forum, 142:1020-

1021, 1988.

(6) Woodward, G. A., and R. N. Baldassano, ``Topical

Diphenhydramine Toxicity in a Five-Year Old with Varicella,''

Pediatric Emergency Care, 4:18-20, 1988.

(7) Letter dated December 14, 1993, from R. G. Kohler, Warner

Lambert Co. to W. E. Gilbertson, FDA, in OTC Vol. 06DTFM, Docket No.

78N-0301, Dockets Management Branch.

[[Page 45772]]

(8) Drug Experience Report No. 698132, OTC Vol. 06DTFM, Docket

No. 78N-0301, Dockets Management Branch.

(9) Chan, C. Y. J., and K. A. Wallander, ``Diphenhydramine

Toxicity in Three Children with Varicella-Zoster Infection,'' The

Annals of Pharmacology, 25:130-132, 1991.

(10) McGann, K. P. et al., ``Diphenhydramine Toxicity in a Child

with Varicella,'' A Case Report, The Journal of Family Practice,

35:210-214, 1992.

V. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). Under the Regulatory

Flexibility Act, if a rule has a significant economic impact on a

substantial number of small entities, an agency must analyze regulatory

options that would minimize any significant economic impact of a rule

on small entities.

Title II of the Unfunded Mandates Reform Act (21 U.S.C. 1501 et

seq.) requires that agencies prepare a written statement and economic

analysis before proposing any rule that may result in an expenditure in

any 1 year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million (adjusted annually for

inflation).

The agency believes that this proposed rule is consistent with the

principles set out in the Executive Order and in these two statutes.

The purpose of this proposed rule is to add warning statements to the

labeling of oral and topical OTC drug products that contain

diphenhydramine. These warning statements concern diphenhydramine

toxicity and are intended to help ensure the safe and effective use of

all OTC drug products that contain this ingredient. Potential benefits

include reduced toxicity when consumers use these products.

This proposed rule amends the final monographs for oral OTC

diphenhydramine drug products for antiemetic, antihistamine,

antitussive, and nighttime sleep-aid indications and will require some

relabeling of these products to add the new warning statement. The

proposed rule also amends the tentative final monograph for OTC

external analgesic drug products and will require some relabeling to

add the new warning statement to products containing diphenhydramine.

The agency's drug listing system identifies approximately 100

manufacturers and 300 marketers of over 800 oral OTC diphenhydramine

drug products, and 10 manufacturers and 50 marketers of over 100

topical OTC diphenhydramine drug products. It is likely that there are

some additional marketers and products that are not currently included

in the agency's system. However, after adjusting for overlap among the

oral and external counts, the agency estimates that there are a total

of 100 manufacturers and 300 marketers of about 1,000 affected stock

keeping units (SKU) (individual products, packages, and sizes).

The agency has been informed that relabeling costs of this type

generally average about $2,000 to $3,000 per SKU. Assuming that there

are about 1,000 affected OTC SKU's in the marketplace, total one-time

costs of relabeling would be $2 to $3 million. The agency believes that

actual costs would be lower for several reasons. First, most of the

label changes will be made by private label manufacturers that tend to

use relatively simple and less expensive labeling. Second, for oral OTC

diphenhydramine drug products, the agency is proposing a 12-month

implementation period that would allow many manufacturers to coordinate

this change with routinely scheduled label printing and/or revisions.

Similarly, labeling changes for external OTC diphenhydramine drug

products would not be required until that monograph is issued and

becomes final. Thus, the relabeling costs for a warning statement on

these products would be mitigated or eliminated. In addition, because

the new warning statement involves only a single sentence,

supplementary labeling (e.g., stick on labeling) could be used for

those oral products not undergoing a new labeling printing within this

1-year period.

The proposed rule would not require any new reporting and

recordkeeping activities. Therefore, no additional professional skills

are needed. There are no other Federal rules that duplicate, overlap,

or conflict with the proposed rule. The agency does not believe that

there are any significant alternatives to the proposed rule that would

adequately provide for the safe and effective OTC use of drug products

that contain diphenhydramine.

This proposed rule may have a significant economic impact on some

small entities. The labeling of many of the affected products is

prepared by private label manufacturers for small marketers. Census

data provide aggregate industry statistics on the total number of

manufacturers for Standardized Industrial Classification Code 2834

Pharmaceutical Preparations by establishment size, but do not

distinguish between manufacturers of prescription and OTC drug

products. According to the U.S. Small Business Administration (SBA)

designations for this industry, over 92 percent of the roughly 700

establishments and over 87 percent of the 650 firms are small. (Because

census size categories do not correspond to the SBA designation of 750

employees, these figures are based on 500 employees.)

An analysis of IMS Co. listings for manufacturers of OTC drug

products found that from 46 to 69 percent of the 400 listed firms are

small using the SBA definition of 750 employees. The agency's drug

listing system indicates that about 300 marketers will need to relabel,

and that this relabeling will be prepared by about 100 entities, most

of which are private label manufacturers. Thus, the agency believes

that most of the manufacturers affected by this proposed rule would be

small.

Because this regulation would affect the information content of all

OTC drug products that contain diphenhydramine, firms that manufacture

or relabel these OTC drug products will need to change the information

panel for each affected SKU. Some of these costs of doing so will be

mitigated because the agency is allowing up to 1 year for oral products

so that the required labeling revision may be made in the normal course

of business. Labeling changes for topical products may be coordinated

with the final monograph for OTC external analgesic drug products.

Among the steps the agency is taking to minimize the impact on small

entities are: (1) To provide enough time for implementation to enable

entities to use up existing labeling stock, and (2) to provide for the

use of supplementary labeling (e.g., stick on labeling) if necessary.

The agency believes that these actions provide substantial flexibility

and reductions in cost for small entities.

The agency considered but rejected several labeling alternatives:

(1) Voluntary relabeling, (2) a longer implementation period, and (3)

an exemption from coverage for small entities. The agency does not

consider any of these approaches acceptable because they do not assure

that consumers will have the most recent needed information for safe

and effective use of OTC diphenhydramine drug products at the earliest

possible time.

[[Page 45773]]

This analysis shows that this proposed rule is not economically

significant under Executive Order 12866 and that the agency has

undertaken important steps to reduce the burden to small entities.

Nevertheless, some entities, especially those private label

manufacturers that provide labeling for a number of the affected

products, may incur significant impacts. Thus, this economic analysis,

together with other relevant sections of this document, serves as the

agency's initial regulatory flexibility analysis, as required under the

Regulatory Flexibility Act. Finally, this analysis shows that the

Unfunded Mandates Act does not apply to the proposed rule because it

would not result in an expenditure in any 1 year by State, local, and

tribal governments, in the aggregate, or by the private sector, of $100

million.

The agency invites public comment regarding any economic impact

that this rulemaking would have on manufacturers of OTC oral and

topical drug products containing diphenhydramine hydrochloride.

Comments regarding the economic impact of this rulemaking on such

manufacturers should be accompanied by appropriate documentation. The

agency is providing a period of 90 days from the date of publication of

this proposed rulemaking in the Federal Register for comments on this

subject to be developed and submitted. 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.

VI. Paperwork Reduction Act of 1995

FDA tentatively concludes that the labeling requirements proposed

in this document for oral and topical OTC drug products are not subject

to review by the Office of Management and Budget because they do not

constitute a ``collection of information'' under the Paperwork

Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the proposed

warning statements are a ``public disclosure of information originally

supplied by the Federal government to the recipient for the purpose of

disclosure to the public'' (5 CFR 1320.3(c)(2)).

VII. Environmental Impact

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.

VIII. Request for Comments

Interested persons may, on or before November 28, 1997, submit

written comments on the proposed regulations to the Dockets Management

Branch (address above). Written comments on the agency's economic

impact determination may be submitted on or before November 28, 1997.

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 Parts 336, 338, 341, 348

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 parts 336, 338, and 341, and 21 CFR part 348 (as

proposed in the Federal Register of February 8, 1983 (48 FR 5852)) be

amended as follows:

PART 336--ANTIEMETIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

1. The authority citation for 21 CFR part 336 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 336.50 is amended by adding new paragraph (c)(8) to read

as follows:

Sec. 336.50 Labeling of antiemetic drug products.

* * * * *

(c) * * *

(8) For products containing diphenhydramine hydrochloride

identified in Sec. 336.10(c). ``Do Not Use'' (these three words in bold

print) ``with any other product containing diphenhydramine, including

one applied topically.''

* * * * *

PART 338--NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER

HUMAN USE

3. The authority citation for 21 CFR part 338 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).

4. Section 338.50 is amended by adding new paragraph (c)(5) to read

as follows:

Sec. 338.50 Labeling of nighttime sleep-aid drug products.

* * * * *

(c) * * *

(5) ``Do Not Use'' (these three words in bold print) ``with any

other product containing diphenhydramine, including one applied

topically.''

* * * * *

PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC

DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

5. The authority citation for 21 CFR part 341 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).

6. Section 341.72 is amended by adding new paragraphs (c)(6)(iv)

and (c)(7) to read as follows:

Sec. 341.72 Labeling of antihistamine drug products.

* * * * *

(c) * * *

(6) * * *

(iv) For products containing diphenhydramine citrate or

diphenhydramine hydrochloride identified in Sec. 341.12(f) and (g).

``Do Not Use'' (these three words in bold print) ``with any other

product containing diphenhydramine, including one applied topically.''

(7) For products containing diphenhydramine citrate or

diphenhydramine hydrochloride identified in Sec. 341.12(f) and (g).

``Do Not Use:'' (these three words in bold print) ``with any other

product containing diphenhydramine, including one applied topically.''

* * * * *

7. Section 341.74 is amended by adding new paragraphs

(c)(4)(viii)(C) and (c)(4)(ix)(C) to read as follows:

Sec. 341.74 Labeling of antitussive drug products.

* * * * *

(c) * * *

(4) * * *

(viii) * * *

(C) ``Do Not Use'' (these three words in bold print) ``with any

other product containing diphenhydramine, including one applied

topically.''

(ix) * * *

(C) ``Do Not Use'' (these three words in bold print) ``with any

other product

[[Page 45774]]

containing diphenhydramine, including one applied topically.''

* * * * *

PART 348--EXTERNAL ANALGESIC DRUG PRODUCTS FOR OVER-THE-COUNTER

HUMAN USE

8. The authority citation for 21 CFR part 348 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).

9. Section 348.50 (as proposed at 48 FR 5852, February 8, 1983) is

amended by adding new paragraph (c)(10) to read as follows:

Sec. 348.50 Labeling of external analgesic drug products.

* * * * *

(c) * * *

(10) For products containing diphenhydramine hydrochloride

identified in Sec. 348.10(c)(1). The following statement shall appear

as the first warning statement under the heading ``Warnings:'' ``Do Not

Use:'' (these three words in bold print) ``on chicken pox, poison ivy,

sunburn, large areas of the body, broken, blistered, or oozing skin,

more often than directed, or with any other product containing

diphenhydramine, even one taken by mouth.''

* * * * *

Dated: August 22, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97-22983 Filed 8-28-97; 8:45 am]

BILLING CODE 4160-01-F