[Federal Register Volume 62, Number 168 (Friday, August 29, 1997)]
[Proposed Rules]
[Pages 45767-45774]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-22983]


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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.

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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 (H<INF>1</INF>) 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 (<greek-m>g/mL), 
which exceeded the therapeutic level of 0.3 <greek-m>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 <greek-m>g/mL. He was lucid by 
noon and by 4 p.m. his diphenhydramine level was 0.6 <greek-m>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 <greek-m>g/mL in the 4-
year-old and 0.96 <greek-m>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/
<greek-m>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 <greek-m>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 
<greek-m>g/mL. Based on laboratory reports, diphenhydramine 
concentrations greater than 0.1 <greek-m>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):
    <bullet> on chicken pox, poison ivy, sunburn
    <bullet> on large areas of the body
    <bullet> on broken, blistered, or oozing skin
    <bullet> more often than directed
    <bullet> 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