WARNINGS
WARNING
Long-term Safety of Topical Calcineurin Inhibitors Has Not
Been Established
Although a causal relationship has not been established, rare cases of
malignancy (e.g., skin and lymphoma) have been reported in patients treated with
topical calcineurin inhibitors, including PROTOPIC Ointment.
Therefore:
- Continuous long-term use of topical calcineurin inhibitors, including
PROTOPIC Ointment, in any age group should be avoided, and application limited
to areas of involvement with atopic dermatitis.
- PROTOPIC Ointment is not indicated for use in children less than 2 years of
age. Only 0.03% PROTOPIC Ointment is indicated for use in children 2-15 years of
age.
Prolonged systemic use of calcineurin inhibitors for sustained
immunosuppression in animal studies and transplant patients following systemic
administration has been associated with an increased risk of infections,
lymphomas, and skin malignancies. These risks are associated with the intensity
and duration of immunosuppression.
Based on the information above and the mechanism of action, there is a
concern about potential risk with the use of topical calcineurin inhibitors,
including PROTOPIC Ointment. While a causal relationship has not been
established, rare cases of skin malignancy and lymphoma have been reported in
patients treated with topical calcineurin inhibitors, including PROTOPIC
Ointment. Therefore:
- PROTOPIC Ointment should not be used in immunocompromised adults and
children.
- If signs and symptoms of atopic dermatitis do not improve within 6 weeks,
patients should be re-examined by their healthcare provider and their diagnosis
be confirmed (see PRECAUTIONS: General).
- The safety of PROTOPIC Ointment has not been established beyond one year of
non-continuous use.
(See
CLINICAL
PHARMACOLOGY, boxed
WARNINGS,
INDICATIONS AND
USAGE, and
DOSAGE AND
ADMINISTRATION).
PRECAUTIONS
General
The use of PROTOPIC Ointment should be avoided on pre-malignant
and malignant skin conditions. Some malignant skin conditions, such as cutaneous
T-cell lymphoma (CTCL), may mimic atopic dermatitis.
The use of PROTOPIC Ointment in patients with Netherton’s Syndrome or other
skin diseases where there is the potential for increased systemic absorption of
tacrolimus is not recommended. The safety of PROTOPIC Ointment has not been
established in patients with generalized erythroderma.
The use of PROTOPIC Ointment may cause local symptoms such as skin burning
(burning sensation, stinging, soreness) or pruritus. Localized symptoms are most
common during the first few days of PROTOPIC Ointment application and typically
improve as the lesions of atopic dermatitis resolve. With PROTOPIC Ointment
0.1%, 90% of the skin burning events had a duration between 2 minutes and 3
hours (median 15 minutes). 90% of the pruritus events had a duration between 3
minutes and 10 hours (median 20 minutes). (see
ADVERSE
REACTIONS).
Bacterial and Viral Skin Infections
Before commencing treatment with PROTOPIC Ointment, cutaneous
bacterial or viral infections at treatment sites should be resolved. Studies
have not evaluated the safety and efficacy of PROTOPIC Ointment in the treatment
of clinically infected atopic dermatitis.
While patients with atopic dermatitis are predisposed to superficial skin
infections including eczema herpeticum (Kaposi’s varicelliform eruption),
treatment with PROTOPIC Ointment may be independently associated with an
increased risk of varicella zoster virus infection (chicken pox or shingles),
herpes simplex virus infection, or eczema herpeticum.
Patients with Lymphadenopathy
In clinical studies, 112/13494 (0.8%) cases of lymphadenopathy
were reported and were usually related to infections (particularly of the skin)
and noted to resolve upon appropriate antibiotic therapy. Of these 112 cases,
the majority had either a clear etiology or were known to resolve. Transplant
patients receiving immunosuppressive regimens (e.g., systemic tacrolimus) are at
increased risk for developing lymphoma; therefore, patients who receive PROTOPIC
Ointment and who develop lymphadenopathy should have the etiology of their
lymphadenopathy investigated. In the absence of a clear etiology for the
lymphadenopathy, or in the presence of acute infectious mononucleosis, PROTOPIC
Ointment should be discontinued. Patients who develop lymphadenopathy should be
monitored to ensure that the lymphadenopathy resolves.
Sun Exposure
During the course of treatment, patients should minimize or avoid
natural or artificial sunlight exposure, even while PROTOPIC is not on the skin.
It is not known whether PROTOPIC Ointment interferes with skin response to
ultraviolet damage.
Immunocompromised Patients
The safety and efficacy of PROTOPIC Ointment in immunocompromised
patients have not been studied.
Renal Insufficiency
Rare post-marketing cases of acute renal failure have been
reported in patients treated with PROTOPIC Ointment. Systemic absorption is more
likely to occur in patients with epidermal barrier defects especially when
PROTOPIC is applied to large body surface areas. Caution should also be
exercised in patients predisposed to renal impairment.
Information for Patients
(See Medication
Guide)
Patients using PROTOPIC Ointment should receive and understand the
information in the Medication Guide. Please refer to the Medication Guide for
providing instruction and information to the patient.
What is the most important information patients should know
about PROTOPIC Ointment?
The safety of using PROTOPIC Ointment for a long period of time is not known.
A very small number of people who have used PROTOPIC Ointment have had cancer
(for example, skin or lymphoma). However, a link with PROTOPIC Ointment has not
been shown. Because of this concern, instruct patients:
- Do not use PROTOPIC Ointment continuously for a long time.
- Use PROTOPIC Ointment only on areas of skin that have eczema.
- Do not use PROTOPIC Ointment on a child under 2 years old.
PROTOPIC Ointment comes in two strengths:
- Only PROTOPIC Ointment 0.03% is for use on children aged 2 to 15 years.
- Either PROTOPIC Ointment 0.03% or 0.1% can be used by adults and children 16
years and older.
Advise patients to talk to their prescriber for more information.
How should PROTOPIC Ointment be used?
Advise patients to:
- Use PROTOPIC Ointment exactly as prescribed.
- Use PROTOPIC Ointment only on areas of skin that have eczema.
- Use PROTOPIC Ointment for short periods, and if needed, treatment may be
repeated with breaks in between.
- Stop PROTOPIC Ointment when the signs and symptoms of eczema, such as
itching, rash, and redness go away, or as directed.
- Follow their doctor’s advice if symptoms of eczema return after treatment
with PROTOPIC Ointment.
- Call their doctor if:
- Their symptoms get worse with PROTOPIC Ointment.
- They get an infection on their skin.
- Their symptoms do not improve after 6 weeks of treatment. Sometimes other
skin diseases can look like eczema.
To apply PROTOPIC Ointment:
Advise patients:
- Wash their hands before applying PROTOPIC.
- Apply a thin layer of PROTOPIC Ointment twice daily to the areas of skin
affected by eczema.
- Use the smallest amount of PROTOPIC Ointment needed to control the signs and
symptoms of eczema.
- If they are a caregiver applying PROTOPIC Ointment to a patient, or if they
are a patient who is not treating their hands, wash their hands with soap and
water after applying PROTOPIC. This should remove any ointment left on the
hands.
- Do not bathe, shower, or swim right after applying PROTOPIC. This could wash
off the ointment.
- Moisturizers can be used with PROTOPIC Ointment. Make sure they check with
their doctor first about the products that are right for them. Because the skin
of patients with eczema can be very dry, it is important to keep up good skin
care practices. If they use moisturizers, apply them after PROTOPIC
Ointment.
What should patients avoid while using PROTOPIC
Ointment?
Advise patients:
- Do not use ultraviolet light therapy, sun lamps, or tanning beds during
treatment with PROTOPIC Ointment.
- Limit sun exposure during treatment with PROTOPIC Ointment even when the
medicine is not on their skin. If patients need to be outdoors after applying
PROTOPIC Ointment, wear loose fitting clothing that protects the treated area
from the sun. Doctors should advise what other types of protection from the sun
patients should use.
- Do not cover the skin being treated with bandages, dressings or wraps.
Patients can wear normal clothing.
- Avoid getting PROTOPIC Ointment in the eyes or mouth. Do not swallow
PROTOPIC Ointment. Patients should call their doctor if they swallow PROTOPIC
Ointment.
Drug Interactions
Formal topical drug interaction studies with PROTOPIC Ointment
have not been conducted. Based on its extent of absorption, interactions of
PROTOPIC Ointment with systemically administered drugs are unlikely to occur but
cannot be ruled out (see
CLINICAL
PHARMACOLOGY). The concomitant administration of known CYP3A4
inhibitors in patients with widespread and/or erythrodermic disease should be
done with caution. Some examples of such drugs are erythromycin, itraconazole,
ketoconazole, fluconazole, calcium channel blockers and cimetidine.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or
mammalian (Chinese hamster lung-derived cells) in
vitro assays of mutagenicity, the in vitro
CHO/HGPRT assay of mutagenicity, or in vivo
clastogenicity assays performed in mice. Tacrolimus did not cause unscheduled
DNA synthesis in rodent hepatocytes.
Oral (feed) carcinogenicity studies have been carried out with systemically
administered tacrolimus in male and female rats and mice. In the 80-week mouse
study and in the 104-week rat study no relationship of tumor incidence to
tacrolimus dosage was found at daily doses up to 3 mg/kg [9X the Maximum
Recommended Human Dose (MRHD) based on AUC comparisons] and 5 mg/kg (3X the MRHD
based on AUC comparisons), respectively.
A 104-week dermal carcinogenicity study was performed in mice with tacrolimus
ointment (0.03% - 3%), equivalent to tacrolimus doses of 1.1-118 mg/kg/day or
3.3-354 mg/m2/day. In the study, the incidence of skin
tumors was minimal and the topical application of tacrolimus was not associated
with skin tumor formation under ambient room lighting. However, a statistically
significant elevation in the incidence of pleomorphic lymphoma in high dose male
(25/50) and female animals (27/50) and in the incidence of undifferentiated
lymphoma in high dose female animals (13/50) was noted in the mouse dermal
carcinogenicity study. Lymphomas were noted in the mouse dermal carcinogenicity
study at a daily dose of 3.5 mg/kg (0.1% tacrolimus ointment) (26X MRHD based on
AUC comparisons). No drug-related tumors were noted in the mouse dermal
carcinogenicity study at a daily dose of 1.1 mg/kg (0.03% tacrolimus ointment)
(10X MRHD based on AUC comparisons).
In a 52-week photocarcinogenicity study, the median time to onset of skin
tumor formation was decreased in hairless mice following chronic topical dosing
with concurrent exposure to UV radiation (40 weeks of treatment followed by 12
weeks of observation) with tacrolimus ointment at ≥0.1% tacrolimus.
Reproductive toxicology studies were not performed with topical tacrolimus.
In studies of oral tacrolimus no impairment of fertility was seen in male and
female rats. Tacrolimus, given orally at 1.0 mg/kg (0.12X MRHD based on body
surface area [BSA]) to male and female rats, prior to and during mating, as well
as to dams during gestation and lactation, was associated with embryolethality
and with adverse effects on female reproduction. Effects on female reproductive
function (parturition) and embryolethal effects were indicated by a higher rate
of pre-implantation loss and increased numbers of undelivered and nonviable
pups. When given at 3.2 mg/kg (0.43X MRHD based on BSA), tacrolimus was
associated with maternal and paternal toxicity as well as reproductive toxicity
including marked adverse effects on estrus cycles, parturition, pup viability,
and pup malformations.
Pregnancy
Teratogenic Effects: Pregnancy
Category C
There are no adequate and well-controlled studies of topically
administered tacrolimus in pregnant women. The experience with PROTOPIC Ointment
when used by pregnant women is too limited to permit assessment of the safety of
its use during pregnancy.
Reproduction studies were carried out with systemically administered
tacrolimus in rats and rabbits. Adverse effects on the fetus were observed
mainly at oral dose levels that were toxic to dams. Tacrolimus at oral doses of
0.32 and 1.0 mg/kg (0.04X-0.12X MRHD based on BSA) during organogenesis in
rabbits was associated with maternal toxicity as well as an increase in
incidence of abortions. At the higher dose only, an increased incidence of
malformations and developmental variations was also seen. Tacrolimus, at oral
doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal
toxicity and caused an increase in late resorptions, decreased numbers of live
births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0
and 3.2 mg/kg (0.04X-0.12X MRHD based on BSA) to pregnant rats after
organogenesis and during lactation, was associated with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies of systemically
administered tacrolimus in pregnant women. Tacrolimus is transferred across the
placenta. The use of systemically administered tacrolimus during pregnancy has
been associated with neonatal hyperkalemia and renal dysfunction. PROTOPIC
Ointment should be used during pregnancy only if the potential benefit to the
mother justifies a potential risk to the fetus.
Nursing Mothers
Although systemic absorption of tacrolimus following topical
applications of PROTOPIC Ointment is minimal relative to systemic
administration, it is known that tacrolimus is excreted in human milk. Because
of the potential for serious adverse reactions in nursing infants from
tacrolimus, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use
PROTOPIC Ointment is not indicated for children
less than 2 years of age.
Only the lower concentration, 0.03%, of PROTOPIC Ointment is recommended for
use as a second-line therapy for short-term and
non-continuous chronic treatment of moderate to severe atopic dermatitis in
non-immunocompromised children 2 to 15 years of age who have failed to respond
adequately to other topical prescription treatments for atopic dermatitis, or
when those treatments are not advisable.
The long-term safety and effects of PROTOPIC Ointment on the developing
immune system are unknown (see boxed WARNING,
WARNINGS
and
INDICATIONS and
USAGE).
Four studies were conducted involving a total of about 4,400 patients 2-15
years of age: one 12-week randomized vehicle-controlled study and three
open-label safety studies of one to three years duration. About 2,500 of these
patients were 2 to 6 years of age.
The most common adverse events from these studies associated with PROTOPIC
Ointment application in pediatric patients were skin burning and pruritus (see
ADVERSE
REACTIONS). In addition to skin burning and pruritus, the less common
events (less than 5%) of varicella zoster (mostly chicken pox), and vesiculobullous
rash were more frequent in patients treated with PROTOPIC Ointment 0.03%
compared to vehicle. In the open-label safety studies, the incidence of adverse
events, including infections, did not increase with increased duration of study
drug exposure or amount of ointment used. In about 4,400 pediatric patients
treated with PROTOPIC Ointment, 24 (0.5%) were reported with eczema herpeticum.
Since the safety and efficacy of PROTOPIC Ointment have not been established in
pediatric patients below 2 years of age, its use in this age group is not
recommended.
In an open-label study, immune response to a 23-valent pneumococcal
polysaccharide vaccine was assessed in 23 children 2 to 12 years old with
moderate to severe atopic dermatitis treated with tacrolimus ointment 0.03%.
Protective antibody titers developed in all patients. Similarly, in a
seven-month, double-blind trial, the vaccination response to meningococcal
serogroup C was equivalent in children 2 to 11 years old with moderate to severe
atopic dermatitis treated with tacrolimus ointment 0.03% (n=121), a
hydrocortisone ointment regimen (n=111), or normal children (n=44).
Geriatric Use
Four hundred and four (404) patients ≥ 65 years old received
PROTOPIC Ointment in phase 3 studies. The adverse event profile for these
patients was consistent with that for other adult patients.
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