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Protopic
Overview
What is Protopic?
PROTOPIC (tacrolimus) Ointment contains tacrolimus, a macrolide
immunosuppressant produced by . It is for topical dermatologic use only. Chemically,
tacrolimus is designated as [3-[3*[(1*,3*,4*)],4*,5*,8*,9,12*,14*,15*,16*,18*,19*,26a*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,
12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-][1,4]
oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone,monohydrate. It has the following
structural formula:
Tacrolimus has an empirical formula of CHNO•HO and a
formula weight of 822.03. Each gram of PROTOPIC Ointment contains (w/w) either
0.03% or 0.1% of tacrolimus in a base of mineral oil, paraffin,
propylene carbonate, white petrolatum and white wax.
What does Protopic look like?
What are the available doses of Protopic?
Sorry No records found.
What should I talk to my health care provider before I take Protopic?
Sorry No records found
How should I use Protopic?
PROTOPIC Ointment, both 0.03% and 0.1% for adults, and only 0.03%
for children aged 2 to 15 years, is indicated as for the short-term and non-continuous chronic treatment of
moderate to severe atopic dermatitis in non-immunocompromised adults and
children who have failed to respond adequately to other topical prescription
treatments for atopic dermatitis, or when those treatments are not
advisable.
PROTOPIC Ointment is not indicated for children younger than
2 years of age (see boxed WARNING, and :
).
PROTOPIC Ointment 0.03% and 0.1%
The safety of PROTOPIC Ointment under occlusion, which may promote systemic
exposure, has not been evaluated. PROTOPIC Ointment should not be used with
occlusive dressings.
PROTOPIC Ointment 0.03%
The safety of PROTOPIC Ointment under occlusion, which may promote systemic
exposure, has not been evaluated. PROTOPIC Ointment should not be used with
occlusive dressings.
What interacts with Protopic?
PROTOPIC (tacrolimus) Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.
What are the warnings of Protopic?
It is not known whether this drug is excreted in human milk.
Since many drugs are so excreted, hydroxyzine should not be given to nursing
mothers.
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:
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:
(See , boxed ,
and ).
What are the precautions of Protopic?
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 ).
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.
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.
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.
The safety and efficacy of PROTOPIC Ointment in immunocompromised
patients have not been studied.
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.
(See )
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:
PROTOPIC Ointment comes in two strengths:
Advise patients to talk to their prescriber for more information.
How should PROTOPIC Ointment be used?
Advise patients to:
To apply PROTOPIC Ointment:
Advise patients:
What should patients avoid while using PROTOPIC
Ointment?
Advise patients:
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 ). 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.
No evidence of genotoxicity was seen in bacterial (and ) or
mammalian (Chinese hamster lung-derived cells) assays of mutagenicity, the
CHO/HGPRT assay of mutagenicity, or
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/m/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.
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.
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.
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 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 ,
and ).
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
). 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).
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.
What are the side effects of Protopic?
No phototoxicity and no photoallergenicity were detected in
clinical studies with 12 and 216 normal volunteers, respectively. One out of 198
normal volunteers showed evidence of sensitization in a contact sensitization
study.
In three 12 week randomized vehicle-controlled studies and four safety
studies, 655 and 9,163 patients respectively, were treated with PROTOPIC
Ointment. The duration of follow-up for adult and pediatric patients in the
safety studies is tabulated below.
The following table depicts the adjusted incidence of adverse events pooled
across the 3 identically designed 12-week controlled studies for patients in
vehicle, PROTOPIC Ointment 0.03%, and PROTOPIC Ointment 0.1% treatment groups.
The table also depicts the unadjusted incidence of adverse events in four safety
studies, regardless of relationship to study drug.
Other adverse events which occurred at an incidence between 0.2% and less
than 1% in clinical studies in the above table include: abnormal vision,
abscess, anaphylactoid reaction, anemia, anorexia, anxiety, arthritis,
arthrosis, bilirubinemia, blepharitis, bone disorder, breast neoplasm benign,
bursitis, cataract NOS, chest pain, chills, colitis, conjunctival edema,
constipation, cramps, cutaneous moniliasis, cystitis, dehydration, dizziness,
dry eyes, dry mouth/nose, dyspnea, ear disorder, ecchymosis, edema, epistaxis,
eye pain, furunculosis, gastritis, gastrointestinal disorder, hernia,
hypercholesterolemia, hypertonia, hypothyroidism, joint disorder, laryngitis,
leukoderma, lung disorder, malaise, migraine, moniliasis, mouth ulceration, nail
disorder, neck pain, neoplasm benign, oral moniliasis, otitis externa,
photosensitivity reaction, rectal disorder, seborrhea, skin carcinoma, skin
discoloration, skin hypertrophy, skin ulcer, stomatitis, tendon disorder,
thinking abnormal, tooth caries, sweating, syncope, tachycardia, taste
perversion, unintended pregnancy, vaginal moniliasis, vaginitis, valvular heart
disease, vasodilatation, and vertigo.
The following adverse reactions have been identified during
postapproval use of PROTOPIC Ointment. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship to drug
exposure.
CNS
Seizures
Neoplasms
Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant
melanoma
Infections
Bullous impetigo, osteomyelitis, septicemia
Renal
Acute renal failure in patients with or without Netherton’s syndrome, renal
impairment
Skin
Rosacea
| Time on Study | Adult | Pediatrics | Total | |||||
| less than 1 year | 4682 | 4481 | 9163 | |||||
| greater than or equal to 1 year | 1185 | 1349 | 2534 | |||||
| greater than or equal to 2 years | 200 | 275 | 475 | |||||
| greater than or equal to 3 years | 118 | 182 | 300 | |||||
| Adult | Pediatric | Adult | Pediatric | Total | ||||
|---|---|---|---|---|---|---|---|---|
| Vehicle(n=212)% | 0.03%TacrolimusOintment(n=210)% | 0.1%TacrolimusOintment(n=209)% | Vehicle(n=116)% | 0.03%TacrolimusOintment(n=118)% | (n-4682)% | (n=4481)% | (n=9163)% | |
| Skin Burning* | 26 | 46 | 58 | 29 | 43 | 28 | 20 | 24 |
| Pruritus* | 37 | 46 | 46 | 27 | 41 | 25 | 19 | 22 |
| Flue-likesymptoms* | 19 | 23 | 31 | 25 | 28 | 22 | 34 | 28 |
| Allergic Reaction | 8 | 12 | 6 | 8 | 4 | 9 | 13 | 11 |
| Skin Erythema | 20 | 25 | 28 | 13 | 12 | 12 | 7 | 9 |
| Headache* | 11 | 20 | 19 | 8 | 5 | 13 | 9 | 11 |
| Skin Infection | 11 | 12 | 5 | 14 | 10 | 9 | 16 | 12 |
| Fever | 4 | 4 | 1 | 13 | 21 | 2 | 14 | 8 |
| Infection | 1 | 1 | 2 | 9 | 7 | 6 | 10 | 8 |
| Cough Increased | 2 | 1 | 1 | 14 | 18 | 3 | 10 | 6 |
| Asthma | 4 | 6 | 4 | 6 | 6 | 4 | 13 | 8 |
| Herpes Simplex | 4 | 4 | 4 | 2 | 0 | 4 | 3 | 3 |
| EczemaHerpeticum | 0 | 1 | 1 | 0 | 2 | 0 | 0 | 0 |
| Pharyngitis | 3 | 3 | 4 | 11 | 6 | 4 | 12 | 8 |
| Accidental Injury | 4 | 3 | 6 | 3 | 6 | 6 | 8 | 7 |
| Pustular Rash | 2 | 3 | 4 | 3 | 2 | 2 | 7 | 5 |
| Folliculitis* | 1 | 6 | 4 | 0 | 2 | 4 | 2 | 3 |
| Rhinitis | 4 | 3 | 2 | 2 | 6 | 2 | 4 | 3 |
| Otis Media | 4 | 0 | 1 | 6 | 12 | 2 | 11 | 6 |
| Sinusitis* | 1 | 4 | 2 | 8 | 3 | 6 | 7 | 6 |
| Diarrhea | 3 | 3 | 4 | 2 | 5 | 2 | 4 | 3 |
| Urticaria | 3 | 3 | 6 | 1 | 1 | 3 | 4 | 4 |
| Lack of DrugEffect | 1 | 1 | 0 | 1 | 1 | 6 | 6 | 6 |
| Bronchitis | 0 | 2 | 2 | 3 | 3 | 4 | 4 | 4 |
| Vomiting | 0 | 1 | 1 | 7 | 6 | 1 | 4 | 3 |
| MaculopapularRash | 2 | 2 | 2 | 3 | 0 | 2 | 1 | 1 |
| Rash* | 1 | 5 | 2 | 4 | 2 | 2 | 3 | 3 |
| Abdominal Pain | 3 | 1 | 1 | 2 | 3 | 1 | 3 | 2 |
| Fungal Dermatitis | 0 | 2 | 1 | 3 | 0 | 2 | 4 | 3 |
| Gastroentesritis | 1 | 2 | 2 | 3 | 0 | 2 | 4 | 3 |
| AlcoholIntolerance* | 0 | 3 | 7 | 0 | 0 | 4 | 0 | 2 |
| Acne* | 2 | 4 | 7 | 1 | 0 | 3 | 2 | 3 |
| Sunburn | 1 | 2 | 1 | 0 | 0 | 2 | 1 | 1 |
| Skin Disorder | 2 | 2 | 1 | 1 | 4 | 2 | 2 | 2 |
| Conjunctivitis | 0 | 2 | 2 | 2 | 1 | 3 | 3 | 3 |
| Pain | 1 | 2 | 1 | 0 | 1 | 2 | 1 | 2 |
| VesiculobullousRash* | 3 | 3 | 2 | 0 | 4 | 2 | 1 | 1 |
| Lymphadenopathy | 2 | 2 | 1 | 0 | 3 | 1 | 2 | 1 |
| Nausea | 4 | 3 | 2 | 0 | 1 | 2 | 1 | 2 |
| Skin Tingling* | 2 | 3 | 8 | 1 | 2 | 2 | 1 | 1 |
| Face Edema | 2 | 2 | 1 | 2 | 1 | 1 | 1 | 1 |
| Dyspepsia* | 1 | 1 | 4 | 0 | 0 | 2 | 2 | 2 |
| Dry Skin | 7 | 3 | 3 | 0 | 1 | 1 | 1 | 1 |
| Hypersthesia* | 1 | 3 | 7 | 0 | 0 | 2 | 0 | 1 |
| Skin NeoplasmBenign | 1 | 1 | 1 | 0 | 0 | 1 | 2 | 2 |
| Back Pain* | 0 | 2 | 2 | 1 | 1 | 3 | 0 | 2 |
| Peripheral Edema | 2 | 4 | 3 | 0 | 0 | 2 | 0 | 1 |
| Varicella Zoster/HerpesZoster | 0 | 1 | 0 | 0 | 5 | 1 | 2 | 2 |
| Contact Dermatitis | 1 | 3 | 3 | 3 | 4 | 2 | 2 | 2 |
| Asthena | 1 | 2 | 3 | 0 | 0 | 1 | 0 | 1 |
| Pneumonia | 0 | 1 | 1 | 2 | 0 | 1 | 3 | 2 |
| Eczema | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 1 |
| Insomnia | 3 | 4 | 3 | 1 | 1 | 2 | 0 | 1 |
| Exfoliative Dermatitis | 3 | 3 | 1 | 0 | 0 | 0 | 1 | 0 |
| Dysmenorrhea | 2 | 4 | 4 | 0 | 0 | 2 | 1 | 1 |
| PeriodontalAbscess | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 1 |
| Myalgia* | 0 | 3 | 2 | 0 | 0 | 2 | 1 | 1 |
| Cyst* | 0 | 1 | 3 | 0 | 0 | 1 | 0 | 1 |
| Cellulitis | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 1 |
| Exacerbation ofUntreated Area | 1 | 0 | 1 | 1 | 0 | 1 | 1 | 1 |
| ProceduralComplication | 1 | 0 | 0 | 1 | 0 | 1 | 1 | 1 |
| Hypertension | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 1 |
| Tooth Disorder | 0 | 1 | 1 | 1 | 0 | 2 | 1 | 1 |
| Arthralgia | 1 | 1 | 3 | 2 | 0 | 2 | 1 | 2 |
| Depression | 1 | 2 | 1 | 0 | 0 | 1 | 0 | 1 |
| Paresthesia | 1 | 3 | 3 | 0 | 0 | 2 | 1 | 2 |
| Alopecia | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 1 |
| Urinary Tract Infection | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 2 |
| Ear Pain | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 1 |
What should I look out for while using Protopic?
PROTOPIC (tacrolimus) Ointment is contraindicated in patients with a history of
hypersensitivity to tacrolimus or any other component of the ointment.
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:
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:
(See , boxed ,
and ).
What might happen if I take too much Protopic?
PROTOPIC Ointment is not for oral use. Oral ingestion of PROTOPIC Ointment may
lead to adverse effects associated with systemic administration of tacrolimus.
If oral ingestion occurs, medical advice should be sought.
How should I store and handle Protopic?
Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). PROTECT FROM LIGHT. KEEP TIGHTLY CLOSED. Sarafem is a registered trademark of Eli Lilly and Company. NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146 NDC54868-5233-1 30 gram laminate tubeNDC 54868-5233-0 100 gram laminate tube Store at room temperature 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Marketed by:Astellas Pharma US, Inc.Deerfield, IL 60015-2548 Manufactured by:Astellas Toyama Co., Ltd. Toyama Plant, 2-178 Kojin-machi, Toyama 930-0809, JapanRelabeling of "Additional Barcode" by:Physicians Total Care, Inc.Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The mechanism of action of tacrolimus in atopic dermatitis is not
known. While the following have been observed, the clinical significance of
these observations in atopic dermatitis is not known. It has been demonstrated
that tacrolimus inhibits T-lymphocyte activation by first binding to an
intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium,
calmodulin, and calcineurin is then formed and the phosphatase activity of
calcineurin is inhibited. This effect has been shown to prevent the
dephosphorylation and translocation of nuclear factor of activated T-cells
(NF-AT), a nuclear component thought to initiate gene transcription for the
formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus
also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF,
and TNF-α, all of which are involved in the early stages of T-cell activation.
Additionally, tacrolimus has been shown to inhibit the release of pre-formed
mediators from skin mast cells and basophils, and to down regulate the
expression of FcεRI on Langerhans cells.
The pooled results from three pharmacokinetic studies in 88 adult
atopic dermatitis patients indicate that tacrolimus is minimally absorbed after
the topical application of PROTOPIC Ointment. Peak tacrolimus blood
concentrations ranged from undetectable to 20 ng/mL after single or multiple
doses of 0.03% and 0.1% PROTOPIC Ointment, with 85% (75/88) of the patients
having peak blood concentrations less than 2 ng/mL. In general as treatment
continued, systemic exposure declined as the skin returned to normal. In
clinical studies with periodic blood sampling, a similar distribution of
tacrolimus blood levels was also observed in adult patients, with 90%
(1253/1391) of patients having a blood concentration less than 2 ng/mL.
The absolute bioavailability of tacrolimus from PROTOPIC in atopic dermatitis
patients is approximately 0.5%. In adults with an average of 53% BSA treated,
exposure (AUC) of tacrolimus from PROTOPIC is approximately 30-fold less than
that seen with oral immunosuppressive doses in kidney and liver transplant
patients.
Mean peak tacrolimus blood concentrations following oral administration (0.3
mg/kg/day) in adult kidney transplant (n=26) and liver transplant (n=17)
patients are 24.2±15.8 ng/mL and 68.5±30.0 ng/mL, respectively. The lowest
tacrolimus blood level at which systemic effects (e.g., immunosuppression) can
be observed is not known.
Systemic levels of tacrolimus have also been measured in pediatric patients
(see ).
The plasma protein binding of tacrolimus is approximately 99% and
is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound
mainly to albumin and alpha-1-acid glycoprotein, and has a high level of
association with erythrocytes. The distribution of tacrolimus between whole
blood and plasma depends on several factors, such as hematocrit, temperature at
the time of plasma separation, drug concentration, and plasma protein
concentration. In a US study, the ratio of whole blood concentration to plasma
concentration averaged 35 (range 12 to 67).
There was no evidence based on blood concentrations that tacrolimus
accumulates systemically upon intermittent topical application for periods of up
to 1 year. As with other topical calcineurin inhibitors, it is not known whether
tacrolimus is distributed into the lymphatic system.
Tacrolimus is extensively metabolized by the mixed-function
oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic
pathway leading to the formation of 8 possible metabolites has been proposed.
Demethylation and hydroxylation were identified as the primary mechanisms of
biotransformation in vitro. The major metabolite identified in incubations with
human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a
31-demethyl metabolite has been reported to have the same activity as
tacrolimus.
The mean clearance following IV administration of tacrolimus is
0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant
patients and adult liver transplant patients, respectively. In man, less than 1%
of the dose administered is excreted unchanged in urine.
In a mass balance study of IV administered radiolabeled tacrolimus to 6
healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal
elimination accounted for 92.4 ± 1.0% and the elimination half-life based on
radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on
tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015
L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg.
When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%.
Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for
2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5
hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The
mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of
tacrolimus 0.172 ± 0.088 L/hr/kg.
In a pharmacokinetic study of 14 pediatric atopic dermatitis
patients, between the ages of 2-5 years, peak blood concentrations of tacrolimus
ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03%
PROTOPIC Ointment, with 86% (12/14) of patients having peak blood concentrations
below 2 ng/mL throughout the study.
The highest peak concentration was observed in one patient with 82% BSA
involvement on day 1 following application of 0.03% PROTOPIC Ointment. The peak
concentrations for this subject were 14.8 ng/mL on day 1 and 4.1 ng/mL on day
14. Mean peak tacrolimus blood concentrations following oral administration in
pediatric liver transplant patients (n = 9) were 48.4± 27.9 ng/mL.
In a similar pharmacokinetic study with 61 enrolled pediatric patients (ages
6 -12 years) with atopic dermatitis, peak tacrolimus blood concentrations ranged
from undetectable to 5.3 ng/mL after single or multiple doses of 0.1% PROTOPIC
Ointment, with 91% (52/57) of evaluable patients having peak blood
concentrations below 2 ng/mL throughout the study period. When detected,
systemic exposure generally declined as treatment continued.
In clinical studies with periodic blood sampling, a similar distribution of
tacrolimus blood levels was also observed, with 98% (509/522) of pediatric
patients having a blood concentration below 2 ng/mL.
The effect of renal insufficiency on the pharmacokinetics of
topically administered tacrolimus has not been evaluated. The mean clearance of
IV administered tacrolimus in patients with renal dysfunction was similar to
that of normal volunteers. On the basis of this information dose-adjustment is
not expected to be needed.
The effect of hepatic insufficiency on the pharmacokinetics of
topically administered tacrolimus has not been evaluated but dose-adjustment is
not expected to be needed.
Non-Clinical Toxicology
PROTOPIC (tacrolimus) Ointment is contraindicated in patients with a history of hypersensitivity to tacrolimus or any other component of the ointment.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:
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:
(See , boxed , and ).
If diazepam is to be combined with other centrally acting agents, careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants.
Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.
Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The lower peak concentrations appear due to a slower rate of absorption, with the time required to achieve peak concentrations on average 20–25 minutes greater in the presence of antacids. However, this difference was not statistically significant.
There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole.
There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.
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 ).
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.
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.
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.
The safety and efficacy of PROTOPIC Ointment in immunocompromised patients have not been studied.
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.
(See )
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:
PROTOPIC Ointment comes in two strengths:
Advise patients to talk to their prescriber for more information.
How should PROTOPIC Ointment be used?
Advise patients to:
To apply PROTOPIC Ointment:
Advise patients:
What should patients avoid while using PROTOPIC Ointment?
Advise patients:
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 ). 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.
No evidence of genotoxicity was seen in bacterial (and ) or mammalian (Chinese hamster lung-derived cells) assays of mutagenicity, the CHO/HGPRT assay of mutagenicity, or 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/m/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.
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.
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.
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 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 , and ).
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 ). 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).
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.
No phototoxicity and no photoallergenicity were detected in clinical studies with 12 and 216 normal volunteers, respectively. One out of 198 normal volunteers showed evidence of sensitization in a contact sensitization study.
In three 12 week randomized vehicle-controlled studies and four safety studies, 655 and 9,163 patients respectively, were treated with PROTOPIC Ointment. The duration of follow-up for adult and pediatric patients in the safety studies is tabulated below.
The following table depicts the adjusted incidence of adverse events pooled across the 3 identically designed 12-week controlled studies for patients in vehicle, PROTOPIC Ointment 0.03%, and PROTOPIC Ointment 0.1% treatment groups. The table also depicts the unadjusted incidence of adverse events in four safety studies, regardless of relationship to study drug.
Other adverse events which occurred at an incidence between 0.2% and less than 1% in clinical studies in the above table include: abnormal vision, abscess, anaphylactoid reaction, anemia, anorexia, anxiety, arthritis, arthrosis, bilirubinemia, blepharitis, bone disorder, breast neoplasm benign, bursitis, cataract NOS, chest pain, chills, colitis, conjunctival edema, constipation, cramps, cutaneous moniliasis, cystitis, dehydration, dizziness, dry eyes, dry mouth/nose, dyspnea, ear disorder, ecchymosis, edema, epistaxis, eye pain, furunculosis, gastritis, gastrointestinal disorder, hernia, hypercholesterolemia, hypertonia, hypothyroidism, joint disorder, laryngitis, leukoderma, lung disorder, malaise, migraine, moniliasis, mouth ulceration, nail disorder, neck pain, neoplasm benign, oral moniliasis, otitis externa, photosensitivity reaction, rectal disorder, seborrhea, skin carcinoma, skin discoloration, skin hypertrophy, skin ulcer, stomatitis, tendon disorder, thinking abnormal, tooth caries, sweating, syncope, tachycardia, taste perversion, unintended pregnancy, vaginal moniliasis, vaginitis, valvular heart disease, vasodilatation, and vertigo.
The following adverse reactions have been identified during postapproval use of PROTOPIC Ointment. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
CNS
Seizures
Neoplasms
Lymphomas, basal cell carcinoma, squamous cell carcinoma, malignant melanoma
Infections
Bullous impetigo, osteomyelitis, septicemia
Renal
Acute renal failure in patients with or without Netherton’s syndrome, renal impairment
Skin
Rosacea
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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