[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 (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