Protopic
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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Protopic 0.03% ointment 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 g of Protopic 0.03% ointment contains 0.3 mg of tacrolimus as tacrolimus monohydrate (0.03%). 
 
Excipient with known effect  
Butylhydroxytoluene (E321) 15 micrograms/g ointment. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Ointment 
 
A white to slightly yellowish ointment. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Protopic 0.03% ointment is indicated in adults, adolescents and children from the age of 2 years. 
 
Flare treatment 
Adults and adolescents (16 years of age and above) 
Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or 
are intolerant of conventional therapies such as topical corticosteroids.  
 
Children (2 years of age and above) 
Treatment of moderate to severe atopic dermatitis in children who failed to respond adequately to 
conventional therapies such as topical corticosteroids. 
 
Maintenance treatment 
Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of 
flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 
or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice 
daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected). 
 
4.2 Posology and method of administration 
 
Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of 
atopic dermatitis. 
 
Protopic is available in two strengths, Protopic 0.03% and Protopic 0.1% ointment. 
 
Posology 
 
Flare treatment 
Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be 
continuous on a long-term basis. 
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of 
the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected. 



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Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of 
recurrence (flares) of the disease symptoms, treatment should be re-initiated. 
 
Adults and adolescents (16 years of age and above) 
Treatment should be started with Protopic 0.1% twice a day and treatment should be continued until 
clearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should be 
restarted. An attempt should be made to reduce the frequency of application or to use the lower 
strength Protopic 0.03% ointment if the clinical condition allows. 
 
Generally, improvement is seen within one week of starting treatment. If no signs of improvement are 
seen after two weeks of treatment, further treatment options should be considered. 
 
Elderly 
Specific studies have not been conducted in older people. However, the clinical experience available 
in this patient population has not shown the necessity for any dosage adjustment. 
 
Paediatric population 
Children (2 years of age and above) should use the lower strength Protopic 0.03% ointment. 
Treatment should be started twice a day for up to three weeks. Afterwards the frequency of application 
should be reduced to once a day until clearance of the lesion (see section 4.4). 
 
Protopic ointment should not be used in children aged below 2 years until further data are available. 
 
Maintenance treatment 
Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions 
cleared, almost cleared or mildly affected) are suitable for maintenance treatment. 
 
Adults and adolescents (16 years of age and above) 
Adult patients should use Protopic 0.1% ointment.  
Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas 
commonly affected by atopic dermatitis to prevent progression to flares. Between applications there 
should be 2–3 days without Protopic treatment. 
 
After 12 months treatment, a review of the patient`s condition should be conducted by the physician 
and a decision taken whether to continue maintenance treatment in the absence of safety data for 
maintenance treatment beyond 12 months. 
 
If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment section 
above). 
 
Elderly 
Specific studies have not been conducted in older people (see flare treatment section above). 
 
Paediatric population 
Children (2 years of age and above) should use the lower strength Protopic 0.03% ointment. 
Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas 
commonly affected by atopic dermatitis to prevent progression to flares. Between applications there 
should be 2–3 days without Protopic treatment. 
The review of the child`s condition after 12 months treatment should include suspension of treatment 
to assess the need to continue this regimen and to evaluate the course of the disease. 
 
Protopic ointment should not be used in children aged below 2 years until further data are available. 
 
Method of administration 
Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin. 
Protopic ointment may be used on any part of the body, including face, neck and flexure areas, except 



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on mucous membranes. Protopic ointment should not be applied under occlusion because this method 
of administration has not been studied in patients (see section 4.4).  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, macrolides in general, or to any of the excipients listed in 
section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a 
solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided 
during use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sun 
protection methods, such as minimisation of the time in the sun, use of a sunscreen product and 
covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that 
are considered to be potentially malignant or pre-malignant.  
 
The development of any new change different from previous eczema within a treated area should be 
reviewed by the physician. 
 
The use of tacrolimus ointment is not recommended in patients with a skin barrier defect, such as 
Netherton’s syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host 
Disease. These skin conditions may increase systemic absorption of tacrolimus. Oral use of tacrolimus 
is also not recommended to treat these skin conditions. Post-marketing cases of increased tacrolimus 
blood level have been reported in these conditions. 
 
Care should be exercised if applying Protopic to patients with extensive skin involvement over an 
extended period of time, especially in children (see section 4.2). Patients, particularly paediatric 
patients should be continuously evaluated during treatment with Protopic with respect to the response 
to treatment and the continuing need for treatment. After 12 months this evaluation should include 
suspension of Protopic treatment in paediatric patients (see section 4.2).  
 
The potential for local immunosuppression (possibly resulting in infections or cutaneous malignancies) 
in the long term (i.e. over a period of years) is unknown (see section 5.1). 
Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, 
prolonged systemic exposure to intense immunosuppression following systemic administration of 
calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin 
malignancies. In patients using tacrolimus ointment, cases of malignancies, including cutaneous (i.e. 
cutaneous T Cell lymphomas) and other types of lymphoma, and skin cancers have been reported (see 
section 4.8) Protopic should not be used in patients with congenital or acquired immunodeficiencies or 
in patients on therapy that cause immunosuppression. 
 
Patients with atopic dermatitis treated with Protopic have not been found to have significant systemic 
tacrolimus levels. 
 
Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases 
were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic 
therapy. Transplant patients receiving immunosuppressive regimens (e.g. systemic tacrolimus) are at 
increased risk for developing lymphoma; therefore patients who receive Protopic and who develop 
lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. 
Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In 
case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In 
the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious 
mononucleosis, discontinuation of Protopic should be considered. 
 
The effect of treatment with Protopic ointment on the developing immune system of children aged 
below 2 years has not been established (see section 4.1). 



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Protopic ointment has not been evaluated for its efficacy and safety in the treatment of clinically 
infected atopic dermatitis. Before commencing treatment with Protopic ointment, clinical infections at 
treatment sites should be cleared. Patients with atopic dermatitis are predisposed to superficial skin 
infections. Treatment with Protopic may be associated with an increased risk of folliculitis and herpes 
viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi’s 
varicelliform eruption) (see section 4.8).  In the presence of these infections, the balance of risks and 
benefits associated with Protopic use should be evaluated. 
 
Emollients should not be applied to the same area within 2 hours of applying Protopic ointment. 
Concomitant use of other topical preparations has not been assessed. There is no experience with 
concomitant use of systemic steroids or immunosuppressive agents.  
 
Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to 
these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.  
 
The use of Protopic ointment under occlusion has not been studied in patients. Occlusive dressings are 
not recommended.  
 
As with any topical medicinal product, patients should wash their hands after application if the hands 
are not intended for treatment.  
 
Tacrolimus is extensively metabolised in the liver and although blood concentrations are low 
following topical therapy, the ointment should be used with caution in patients with hepatic failure 
(see section 5.2).  
 
Excipients warnings 
Protopic ointment contains butylhydroxytoluene (E321) as an excipient, which may cause local skin 
reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Formal topical drug interaction studies with tacrolimus ointment have not been conducted. 
 
Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous 
interactions that could affect the metabolism of tacrolimus. 
 
Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4). 
Systemic exposure from topical application of tacrolimus ointment is low (<1.0 ng/ml) and is unlikely 
to be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, the 
possibility of interactions cannot be ruled out and the concomitant systemic administration of known 
CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with 
widespread and/or erythrodermic disease should be done with caution. 
 
Paediatric population 
An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C has 
been investigated in children aged 2-11 years. No effect on immediate response to vaccination, the 
generation of immune memory, or humoral and cell-mediated immunity has been observed (see 
section 5.1). 
 
4.6 Fertility, Pregnancy and lactation 
 
Pregnancy 
There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals 
have shown reproductive toxicity following systemic administration (see section 5.3). The potential 
risk for humans is unknown. 
 



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Protopic ointment should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk. 
Although clinical data have shown that systemic exposure from application of tacrolimus ointment is 
low, breast-feeding during treatment with Protopic ointment is not recommended. 
 
Fertility 
There are no fertility data available. 
 
4.7 Effects on ability to drive and use machines 
 
Protopic ointment has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
In clinical studies approximately 50% of patients experienced some type of skin irritation adverse 
reaction at the site of application. Burning sensation and pruritus were very common, usually mild to 
moderate in severity and tended to resolve within one week of starting treatment. Erythema was a 
common skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site of 
application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation after 
consumption of an alcoholic beverage) was common. 
Patients may be at an increased risk of folliculitis, acne and herpes viral infections. 
 
Adverse reactions with suspected relationship to treatment are listed below by system organ class. 
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon 
(≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
System Organ 
Class 

Very Common 
≥1/10 

Common 
≥1/100, 
<1/10 

Uncommon 
≥1/1000, 
<1/100 

Not known 
(cannot be 
estimated 
from the 
available 
data) 

Infections and 
infestations 

 Local skin infection 
regardless of specific 
aetiology including but not 
limited to:  
Eczema herpeticum,  
Folliculitis,  
Herpes simplex,  
Herpes virus infection,  
Kaposi’s varicelliform 
eruption* 

 Ophthalmic 
Herpes 
Infection* 

Metabolism and 
nutrition 
disorders 

 Alcohol intolerance (facial 
flushing or skin irritation 
after consumption of an 
alcoholic beverage) 

  

Nervous system 
disorders 

 Paraesthesias and 
dysaesthesias 
(hyperaesthesia, burning 
sensation) 

  

Skin and 
subcutaneous 
tissue disorders 

 Pruritus 
 

Acne* Rosacea* 
Lentigo* 

General disorders Application site Application site warmth,   Application 



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and 
administration 
site conditions 

burning,  
Application site 
pruritus 

Application site erythema,  
Application site pain,  
Application site irritation,  
Application site 
paraesthesia,  
Application site rash 
 

site oedema* 

Investigations    Drug level 
increased* 
(see section 
4.4) 

*The adverse reaction has been reported during post-marketing experience 
 
Post-marketing 
Cases of malignancies, including cutaneous (i.e. cutaneous T Cell lymphomas) and other types of 
lymphoma, and skin cancers, have been reported in patients using tacrolimus ointment (see 
section 4.4).  
 
Maintenance treatment 
In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and 
severe atopic dermatitis the following adverse events were noted to occur more frequently than in the 
control group: application site impetigo (7.7% in children) and application site infections (6.4% in 
children and 6.3% in adults). 
 
Paediatric population 
Frequency, type and severity of adverse reactions in children are similar to those reported in adults. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdosage following topical administration is unlikely.  
If ingested, general supportive measures may be appropriate. These may include monitoring of vital 
signs and observation of clinical status. Due to the nature of the ointment vehicle, induction of 
vomiting or gastric lavage is not recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AH01 
 
Mechanism of action and pharmacodynamic effects 
The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the 
following have been observed, the clinical significance of these observations in atopic dermatitis is not 
known. 
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-
dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis 
of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ. 
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory 
activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory 
mediators from skin mast cells, basophils and eosinophils. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous 
dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin 
thickness and did not cause skin atrophy in animals. 

In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus 
ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of 
their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis 
in humans.  
 
Clinical efficacy and safety 
The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus 
ointment in Phase I to Phase III clinical trials. Data from six major trials are presented here. 
 
In a six-month multicentre double-blind randomised trial, 0.1% tacrolimus ointment was administered 
twice-a-day to adults with moderate to severe atopic dermatitis and compared to a topical 
corticosteroid based regimen (0.1% hydrocortisone butyrate on trunk and extremities, 1% 
hydrocortisone acetate on face and neck). The primary endpoint was the response rate at month 3 
defined as the proportion of patients with at least 60% improvement in the mEASI (modified Eczema 
Area and Severity Index) between baseline and month 3. The response rate in the 0.1% tacrolimus 
group (71.6%) was significantly higher than that in the topical corticosteroid based treatment group 
(50.8%; p<0.001; Table 1). The response rates at month 6 were comparable to the 3-month results.  
 
Table 1: Efficacy at month 3 
 Topical corticosteroid 

regimen§ 
(N=485) 

Tacrolimus 0.1% 
(N=487) 

Response rate of ≥ 60% 
improvement in mEASI (Primary 
Endpoint)§§ 

50.8% 71.6% 

Improvement ≥ 90% in Physician’s 
Global Evaluation 

28.5% 47.7% 

§ Topical corticosteroid regimen = 0.1% hydrocortisone butyrate on trunk and extremities, 1% 
hydrocortisone acetate on face and neck 
§§ higher values = greater improvement 
 
The incidence and nature of most adverse events were similar in the two treatment groups. Skin 
burning, herpes simplex, alcohol intolerance (facial flushing or skin sensitivity after alcohol intake), 
skin tingling, hyperaesthesia, acne and fungal dermatitis occurred more often in the tacrolimus 
treatment group. There were no clinically relevant changes in the laboratory values or vital signs in 
either treatment group throughout the study. 
 
In the second trial, children aged from 2 to 15 years with moderate to severe atopic dermatitis received 
twice daily treatment for three weeks of 0.03% tacrolimus ointment, 0.1% tacrolimus ointment or 1% 
hydrocortisone acetate ointment. The primary endpoint was the area-under-the-curve (AUC) of the 
mEASI as a percentage of baseline averaged over the treatment period. The results of this multicentre, 
double-blind, randomised trial showed that tacrolimus ointment, 0.03% and 0.1%, is significantly 
more effective (p<0.001 for both) than 1% hydrocortisone acetate ointment (Table 2). 
 
Table 2: Efficacy at week 3 
 
 

Hydrocortisone 
acetate 1% 
(N=185) 

Tacrolimus 0.03% 
(N=189) 

Tacrolimus 0.1% 
(N=186) 

Median mEASI as Percentage of 
Baseline mean AUC (Primary 
Endpoint)§ 

64.0% 44.8% 39.8% 

Improvement ≥ 90% in Physician’s 
Global Evaluation 

15.7% 38.5% 48.4% 



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§ lower values = greater improvement 
 
The incidence of local skin burning was higher in the tacrolimus treatment groups than in the 
hydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in the 
hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs 
in either treatment group throughout the clinical trial. 
 
The purpose of the third multicentre, double-blind, randomised study was the assessment of efficacy 
and safety of 0.03% tacrolimus ointment applied once or twice a day relative to twice daily 
administration of 1% hydrocortisone acetate ointment in children with moderate to severe atopic 
dermatitis. Treatment duration was for up to three weeks. 
 
Table 3: Efficacy at week 3 
 
 

Hydrocortisone 
acetate 1% 
Twice daily 
(N=207) 

Tacrolimus 0.03% 
Once daily (N=207) 

Tacrolimus 0.03% 
Twice daily (N=210) 

Median mEASI Percentage 
Decrease (Primary Endpoint)§ 

47.2% 70.0% 78.7% 

Improvement ≥ 90% in 
Physician’s Global Evaluation  

13.6% 27.8% 36.7% 

§ higher values = greater improvement 
 
The primary endpoint was defined as the percentage decrease in mEASI from the baseline to end of 
treatment. A statistically significant better improvement was shown for once daily and twice daily 
0.03% tacrolimus ointment compared to twice daily hydrocortisone acetate ointment (p<0.001 for 
both). Twice daily treatment with 0.03% tacrolimus ointment was more effective than once daily 
administration (Table 3). The incidence of local skin burning was higher in the tacrolimus treatment 
groups than in the hydrocortisone group. There were no clinically relevant changes in the laboratory 
values or vital signs in either treatment group throughout the study. 
 
In the fourth trial, approximately 800 patients (aged ≥2 years) received 0.1% tacrolimus ointment 
intermittently or continuously in an open-label, long-term safety study for up to four years, with 300 
patients receiving treatment for at least three years and 79 patients receiving treatment for a minimum 
of 42 months. Based on changes from baseline in EASI score and body surface area affected, patients 
regardless of age had improvement in their atopic dermatitis at all subsequent time points. In addition, 
there was no evidence of loss of efficacy throughout the duration of the clinical trial. The overall 
incidence of adverse events tended to decrease as the study progressed for all patients independent of 
age. The three most common adverse events reported were flu-like symptoms (cold, common cold, 
influenza, upper respiratory infection, etc.), pruritus and skin burning. No adverse events previously 
unreported in shorter duration and/or previous studies were observed in this long-term study. 
 
The efficacy and safety of tacrolimus ointment in maintenance treatment of mild to severe atopic 
dermatitis was assessed in 524 patients in two Phase III multicentre clinical trials of similar design, 
one in adult patients (≥16 years) and one in paediatric patients (2-15 years). In both studies, patients 
with active disease entered an open-label period (OLP) during which they treated affected lesions with 
tacrolimus ointment twice daily until improvement had reached a predefined score (Investigator’s 
Global Assessment [IGA] ≤2, i.e. clear, almost clear or mild disease) for a maximum of 6 weeks. 
Thereafter, patients entered a double-blind disease control period (DCP) for up to 12 months. Patients 
were randomised to receive either tacrolimus ointment (0.1% adults; 0.03% children) or vehicle, once 
a day twice weekly on Mondays and Thursdays. If a disease exacerbation occurred, patients were 
treated with open-label tacrolimus ointment twice daily for a maximum of 6 weeks until the IGA score 
returned to ≤2. 
The primary endpoint in both studies was the number of disease exacerbations requiring a “substantial 
therapeutic intervention” during the DCP, defined as an exacerbation with an IGA of 3-5 (i.e. 
moderate, severe and very severe disease) on the first day of the flare, and requiring more than 7 days 
treatment. Both studies showed significant benefit with twice weekly treatment with tacrolimus 



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ointment with regard to the primary and key secondary endpoints over a period of 12 months in a 
pooled population of patients with mild to severe atopic dermatitis. In a subanalysis of a pooled 
population of patients with moderate to severe atopic dermatitis these differences remained 
statistically significant (Table 4). No adverse events not reported previously were observed in these 
studies. 
 
Table 4: Efficacy (moderate to severe subpopulation) 

 
 

Adults, ≥16 years Children, 2-15 years 
Tacrolimus 0.1% 
Twice weekly 
(N=80) 

Vehicle 
Twice weekly 
(N=73) 

Tacrolimus 
0.03% 
Twice weekly 
(N=78) 

Vehicle 
Twice weekly 
(N=75) 

Median number of DEs 
requiring substantial 
intervention adjusted for 
time at risk (% of patients 
without DE requiring 
substantial intervention)  

 
1.0 (48.8%) 

 
5.3 (17.8%) 

 
1.0 (46.2%) 

 
2.9 (21.3%) 

Median time to first DE 
requiring substantial 
intervention 

142 days 15 days 217 days 36 days 

Median number of DEs 
adjusted for time at risk 
(% of patients without any 
DE periods) 

 
1.0 (42.5%) 

 
6.8 (12.3%) 

 
1.5 (41.0%) 

 
3.5 (14.7%) 

Median time to first DE  123 days 14 days 146 days 17 days 
Mean (SD) percentage of 
days of DE exacerbation 
treatment 

16.1 (23.6) 39.0 (27.8) 16.9 (22.1) 29.9 (26.8) 

DE: disease exacerbation 
P<0.001 in favour of tacrolimus ointment 0.1% (adults) and 0.03% (children) for the primary and key 
secondary endpoints  
 
A seven-month, double blind, randomised parallel group study of paediatric patients (2-11 years) with 
moderate to severe atopic dermatitis was performed. In one arm patients received Protopic 0.03% 
ointment (n=121) twice a day for 3 weeks and thereafter once a day until clearance. In the comparator 
arm patients received 1% hydrocortisone acetate ointment (HA) for head and neck and 0.1% 
hydrocortisone butyrate ointment for trunk and limbs (n=111) twice a day for 2 weeks and 
subsequently HA twice a day to all affected areas. During this period all patients and control subjects 
(n=44) received a primary immunisation and a rechallenge with a protein-conjugate vaccine against 
Neisseria menigitidis serogroup C. 
The primary endpoint of this study was the response rate to vaccination, defined as the percentage of 
patients with a serum bactericidal antibody (SBA) titre ≥8 at the week 5 visit. Analysis of the response 
rate at week 5 showed equivalence between the treatment groups (hydrocortisone 98.3%, tacrolimus 
ointment 95.4%; 7-11 years: 100% in both arms). The results in the control group were similar. 
The primary response to vaccination was not affected. 
 
5.2 Pharmacokinetic properties 
 
Clinical data have shown that tacrolimus concentrations in systemic circulation after topical 
administration are low and, when measurable, transient. 
 
Absorption 
Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimus 
following single or repeated topical application of tacrolimus ointment. 
Most atopic dermatitis patients (adults and children) treated with single or repeated application of 
tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment 



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(0.03%) had blood concentrations <1.0 ng/ml. When observed, blood concentrations exceeding 
1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. However, both 
the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and 
children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus 
from Protopic is approximately 30-fold less than that seen with oral immunosuppressive doses in 
kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic 
effects can be observed is not known.  
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated 
for prolonged periods (up to one year) with tacrolimus ointment.  
 
Distribution 
As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to 
plasma proteins is considered not to be clinically relevant. 
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin 
with minimal diffusion into the systemic circulation. 
 
Biotransformation 
Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is 
extensively metabolised in the liver via CYP3A4. 
 
Elimination 
When administered intravenously, tacrolimus has been shown to have a low clearance rate. The 
average total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically available 
tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-
treated with drugs that are potent inhibitors of CYP3A4. 
Following repeated topical application of the ointment the average half-life of tacrolimus was 
estimated to be 75 hours for adults and 65 hours for children. 
 
Paediatric population 
The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, 
with minimal systemic exposure and no evidence of accumulation (see above). 
 
5.3 Preclinical safety data 
 
Repeated dose toxicity and local tolerance 
Repeated topical administration of tacrolimus ointment or the ointment vehicle to rats, rabbits and 
micropigs was associated with slight dermal changes such as erythema, oedema and papules.  
Long-term topical treatment of rats with tacrolimus led to systemic toxicity including alterations of 
kidneys, pancreas, eyes and nervous system. The changes were caused by high systemic exposure of 
rodents resulting from high transdermal absorption of tacrolimus. Slightly lower body weight gain in 
females was the only systemic change observed in micropigs at high ointment concentrations (3%). 
Rabbits were shown to be especially sensitive to intravenous administration of tacrolimus, reversible 
cardiotoxic effects being observed. 
 
Mutagenicity 
In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus. 
 
Carcinogenicity 
Systemic carcinogenicity studies in mice (18 months) and rats (24 months) revealed no carcinogenic 
potential of tacrolimus.  
In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumours 
were observed. In the same study an increased incidence of lymphoma was detected in association 
with high systemic exposure. 
In a photocarcinogenicity study, albino hairless mice were chronically treated with tacrolimus 
ointment and UV radiation. Animals treated with tacrolimus ointment showed a statistically significant 
reduction in time to skin tumour (squamous cell carcinoma) development and an increase in the 
number of tumours. It is unclear whether the effect of tacrolimus is due to systemic 



12 

immunosuppression or a local effect. The risk for humans cannot be completely ruled out as the 
potential for local immunosuppression with the long-term use of tacrolimus ointment is unknown.  
 
Reproduction toxicity 
Embryo/foetal toxicity was observed in rats and rabbits, but only at doses that caused significant 
toxicity in maternal animals. Reduced sperm function was noted in male rats at high subcutaneous 
doses of tacrolimus. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
White soft paraffin 
Liquid paraffin 
Propylene carbonate 
White beeswax 
Hard paraffin 
Butylhydroxytoluene (E321) 
All-rac-α-tocopherol 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
6.5 Nature and contents of container 
 
Laminate tube with an inner lining of low-density-polyethylene fitted with a white polypropylene 
screw cap. 
 
Package sizes: 10 g, 30 g and 60 g. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 



13 

 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/201/001 
EU/1/02/201/002 
EU/1/02/201/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 February 2002 
Date of latest renewal: 20 November 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


14 

1. NAME OF THE MEDICINAL PRODUCT 
 
Protopic 0.1% ointment 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 g of Protopic 0.1% ointment contains 1.0 mg of tacrolimus as tacrolimus monohydrate (0.1%). 
 
Excipient with known effect  
Butylhydroxytoluene (E321) 15 micrograms/g ointment. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Ointment 
 
A white to slightly yellowish ointment. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Protopic 0.1 % ointment is indicated in adults and adolescents (16 years of age and above)  
 
Flare treatment 
Adults and adolescents (16 years of age and above)  
Treatment of moderate to severe atopic dermatitis in adults who are not adequately responsive to or 
are intolerant of conventional therapies such as topical corticosteroids. 
 
Maintenance treatment 
Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation of 
flare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4 
or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twice 
daily tacrolimus ointment (lesions cleared, almost cleared or mildly affected). 
 
4.2 Posology and method of administration 
 
Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment of 
atopic dermatitis. 
 
Protopic is available in two strengths, Protopic 0.03 % and Protopic 0.1 % ointment. 
 
Posology 
 
Flare treatment 
Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be 
continuous on a long-term basis. 
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region of 
the skin should be treated with Protopic until lesions are cleared, almost cleared or mildly affected. 
Thereafter, patients are considered suitable for maintenance treatment (see below). At the first signs of 
recurrence (flares) of the disease symptoms, treatment should be re-initiated. 
 
Adults and adolescents (16 years of age and above) 



15 

Treatment should be started with Protopic 0.1% twice a day and treatment should be continued until 
clearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should be 
restarted. An attempt should be made to reduce the frequency of application or to use the lower 
strength Protopic 0.03% ointment if the clinical condition allows.  
 
Generally, improvement is seen within one week of starting treatment. If no signs of improvement are 
seen after two weeks of treatment, further treatment options should be considered. 
 
Elderly 
Specific studies have not been conducted in older people. However, the clinical experience available 
in this patient population has not shown the necessity for any dosage adjustment. 
 
Paediatric population 
Only Protopic 0.03 % ointment should be used in children from the age of 2 to 16 years.  
Protopic ointment should not be used in children aged below 2 years until further data are available. 
 
Maintenance treatment 
Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesions 
cleared, almost cleared or mildly affected) are suitable for maintenance treatment. 
 
Adults and adolescents (16 years of age and above) 
Adult patients (16 years of age and above) should use Protopic 0.1% ointment. Protopic ointment 
should be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affected 
by atopic dermatitis to prevent progression to flares. Between applications there should be 2–3 days 
without Protopic treatment. 
 
After 12 months treatment, a review of the patient`s condition should be conducted by the physician 
and a decision taken whether to continue maintenance treatment in the absence of safety data for 
maintenance treatment beyond 12 months.  
 
If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment section 
above). 
 
Elderly 
Specific studies have not been conducted in older people (see flare treatment section above). 
 
Paediatric population 
Only Protopic 0.03 % ointment should be used in children from the age of 2 to 16 years.  
Protopic ointment should not be used in children aged below 2 years until further data are available. 
 
Method of administration 
Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin. 
Protopic ointment may be used on any part of the body, including face, neck and flexure areas, except 
on mucous membranes. Protopic ointment should not be applied under occlusion because this method 
of administration has not been studied in patients (see section 4.4).  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, macrolides in general, or to any of the excipients listed in 
section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from a 
solarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoided 
during use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sun 
protection methods, such as minimisation of the time in the sun, use of a sunscreen product and 



16 

covering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions that 
are considered to be potentially malignant or pre-malignant. 
 
The development of any new change different from previous eczema within a treated area should be 
reviewed by the physician. 
 
The use of tacrolimus ointment is not recommended in patients with a skin barrier defect, such as 
Netherton’s syndrome, lamellar ichthyosis, generalized erythroderma or cutaneous Graft Versus Host 
Disease. These skin conditions may increase systemic absorption of tacrolimus. Oral use of tacrolimus 
is also not recommended to treat these skin conditions. Post-marketing cases of increased tacrolimus 
blood level have been reported in these conditions.  
 
Care should be exercised if applying Protopic to patients with extensive skin involvement over an 
extended period of time, especially in children (see section 4.2).  
Patients, particularly paediatric patients should be continuously evaluated during treatment with 
Protopic with respect to the response to treatment and the continuing need for treatment. After 12 
months this evaluation should include suspension of Protopic treatment in paediatric patients (see 
section 4.2). 
 
The potential for local immunosuppression (possibly resulting in infections or cutaneous malignancies) 
in the long term (i.e. over a period of years) is unknown (see section 5.1). 
Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, 
prolonged systemic exposure to intense immunosuppression following systemic administration of 
calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin 
malignancies. In patients using tacrolimus ointment, cases of malignancies, including cutaneous (i.e. 
cutaneous T Cell lymphomas)  and other types of lymphoma, and skin cancers have been reported (see 
section 4.8). Protopic should not be used in patients with congenital or acquired immunodeficiencies 
or in patients on therapy that cause immunosuppression. 
 
Patients with atopic dermatitis treated with Protopic have not been found to have significant systemic 
tacrolimus levels.  
 
Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases 
were related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotic 
therapy. Transplant patients receiving immunosuppressive regimens (e.g. systemic tacrolimus) are at 
increased risk for developing lymphoma; therefore patients who receive Protopic and who develop 
lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. 
Lymphadenopathy present at initiation of therapy should be investigated and kept under review. In 
case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should be investigated. In 
the absence of a clear aetiology for the lymphadenopathy or in the presence of acute infectious 
mononucleosis, discontinuation of Protopic should be considered. 
 
Protopic ointment has not been evaluated for its efficacy and safety in the treatment of clinically 
infected atopic dermatitis. Before commencing treatment with Protopic ointment, clinical infections at 
treatment sites should be cleared. Patients with atopic dermatitis are predisposed to superficial skin 
infections. Treatment with Protopic may be associated with an increased risk of folliculitis and herpes 
viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi’s 
varicelliform eruption) (see section 4.8). In the presence of these infections, the balance of risks and 
benefits associated with Protopic use should be evaluated. 
 
Emollients should not be applied to the same area within 2 hours of applying Protopic ointment. 
Concomitant use of other topical preparations has not been assessed. There is no experience with 
concomitant use of systemic steroids or immunosuppressive agents.  
 
Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to 
these areas, the ointment should be thoroughly wiped off and/or rinsed off with water.  
 



17 

The use of Protopic ointment under occlusion has not been studied in patients. Occlusive dressings are 
not recommended.  
 
As with any topical medicinal product, patients should wash their hands after application if the hands 
are not intended for treatment.  
 
Tacrolimus is extensively metabolised in the liver and although blood concentrations are low 
following topical therapy, the ointment should be used with caution in patients with hepatic failure 
(see section 5.2).  
 
Excipients warnings 
Protopic ointment contains butylhydroxytoluene (E321) as an excipient, which may cause local skin 
reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Formal topical drug interaction studies with tacrolimus ointment have not been conducted. 
 
Tacrolimus is not metabolised in human skin, indicating that there is no potential for percutaneous 
interactions that could affect the metabolism of tacrolimus. 
 
Systemically available tacrolimus is metabolised via the hepatic Cytochrome P450 3A4 (CYP3A4). 
Systemic exposure from topical application of tacrolimus ointment is low (< 1.0 ng/ml) and is unlikely 
to be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, the 
possibility of interactions cannot be ruled out and the concomitant systemic administration of known 
CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients with 
widespread and/or erythrodermic disease should be done with caution. 
 
Paediatric population 
An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C has 
been investigated in children aged 2-11 years. No effect on immediate response to vaccination, the 
generation of immune memory, or humoral and cell-mediated immunity has been observed (see 
section 5.1). 
 
4.6 Fertility, Pregnancy and lactation 
 
Pregnancy 
There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals 
have shown reproductive toxicity following systemic administration (see section 5.3). The potential 
risk for humans is unknown. 
 
Protopic ointment should not be used during pregnancy unless clearly necessary. 
 
Breast-feeding 
Human data demonstrate that, after systemic administration, tacrolimus is excreted into breast milk. 
Although clinical data have shown that systemic exposure from application of tacrolimus ointment is 
low, breast-feeding during treatment with Protopic ointment is not recommended. 
 
Fertility 
There are no fertility data available. 
 
4.7 Effects on ability to drive and use machines 
 
Protopic ointment has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 



18 

In clinical studies approximately 50% of patients experienced some type of skin irritation adverse 
reaction at the site of application. Burning sensation and pruritus were very common, usually mild to 
moderate in severity and tended to resolve within one week of starting treatment. Erythema was a 
common skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site of 
application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation after 
consumption of an alcoholic beverage) was common. 
 
Patients may be at an increased risk of folliculitis, acne and herpes viral infections. 
Adverse reactions with suspected relationship to treatment are listed below by system organ class. 
Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) and uncommon 
(≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of 
decreasing seriousness. 
 
System Organ 
Class 

Very Common 
≥1/10 

Common 
≥1/100, 
<1/10 

Uncommon 
≥1/1000, 
<1/100 

Not known 
(cannot be 
estimated 
from the 
available 
data) 

Infections and 
infestations 

 Local skin infection 
regardless of specific 
aetiology including but not 
limited to:  
Eczema herpeticum,  
Folliculitis,  
Herpes simplex,  
Herpes virus infection,  
Kaposi’s varicelliform 
eruption* 

 Ophthalmic 
Herpes 
Infection* 

Metabolism and 
nutrition 
disorders 

 Alcohol intolerance (facial 
flushing or skin irritation 
after consumption of an 
alcoholic beverage) 

  

Nervous system 
disorders 

 Paraesthesias and 
dysaesthesias 
(hyperaesthesia, burning 
sensation) 

  

Skin and 
subcutaneous 
tissue disorders 

 Pruritus 
 

Acne* Rosacea* 
Lentigo* 

General disorders 
and 
administration 
site conditions 

Application site 
burning,  
Application site 
pruritus 

Application site warmth,  
Application site erythema,  
Application site pain,  
Application site irritation,  
Application site 
paraesthesia,  
Application site rash 
 

 Application 
site oedema* 

Investigations    Drug level 
increased* 
(see section 
4.4) 

*The adverse reaction has been reported during post-marketing experience 
 
Post-marketing 



19 

Cases of malignancies, including cutaneous (i.e. cutaneous T Cell lymphomas) and other types of 
lymphoma, and skin cancers, have been reported in patients using tacrolimus ointment (see 
section 4.4).  
 
Maintenance treatment 
In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate and 
severe atopic dermatitis the following adverse events were noted to occur more frequently than in the 
control group: application site impetigo (7.7% in children) and application site infections (6.4% in 
children and 6.3% in adults). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Overdosage following topical administration is unlikely.  
If ingested, general supportive measures may be appropriate. These may include monitoring of vital 
signs and observation of clinical status. Due to the nature of the ointment vehicle, induction of 
vomiting or gastric lavage is not recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AH01 
 
Mechanism of action and pharmacodynamic effects 
The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While the 
following have been observed, the clinical significance of these observations in atopic dermatitis is not 
known. 
Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-
dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis 
of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-α and IFN-γ. 
In vitro, in Langerhans cells isolated from normal human skin, tacrolimus reduced the stimulatory 
activity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatory 
mediators from skin mast cells, basophils and eosinophils. 

In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous 
dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin 
thickness and did not cause skin atrophy in animals. 

In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus 
ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of 
their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis 
in humans.  
 
Clinical efficacy and safety 
The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimus 
ointment in Phase I to Phase III clinical trials. Data from six major trials are presented here. 
 
In a six-month multicentre double-blind randomised trial, 0.1% tacrolimus ointment was administered 
twice-a-day to adults with moderate to severe atopic dermatitis and compared to a topical 
corticosteroid based regimen (0.1% hydrocortisone butyrate on trunk and extremities, 1% 
hydrocortisone acetate on face and neck). The primary endpoint was the response rate at month 3 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


20 

defined as the proportion of patients with at least 60% improvement in the mEASI (modified Eczema 
Area and Severity Index) between baseline and month 3. The response rate in the 0.1% tacrolimus 
group (71.6%) was significantly higher than that in the topical corticosteroid based treatment group 
(50.8%; p<0.001; Table 1). The response rates at month 6 were comparable to the 3-month results.  
 
Table 1: Efficacy at month 3 
 Topical corticosteroid 

regimen§ 
(N=485) 

Tacrolimus 0.1% 
(N=487) 

Response rate of ≥ 60% 
improvement in mEASI (Primary 
Endpoint)§§ 

50.8% 71.6% 

Improvement ≥ 90% in Physician’s 
Global Evaluation 

28.5% 47.7% 

§ Topical corticosteroid regimen = 0.1% hydrocortisone butyrate on trunk and extremities, 1% 
hydrocortisone acetate on face and neck 
§§ higher values = greater improvement 
 
The incidence and nature of most adverse events were similar in the two treatment groups. Skin 
burning, herpes simplex, alcohol intolerance (facial flushing or skin sensitivity after alcohol intake), 
skin tingling, hyperaesthesia, acne and fungal dermatitis occurred more often in the tacrolimus 
treatment group. There were no clinically relevant changes in the laboratory values or vital signs in 
either treatment group throughout the study. 
 
In the second trial, children aged from 2 to 15 years with moderate to severe atopic dermatitis received 
twice daily treatment for three weeks of 0.03% tacrolimus ointment, 0.1% tacrolimus ointment or 1% 
hydrocortisone acetate ointment. The primary endpoint was the area-under-the-curve (AUC) of the 
mEASI as a percentage of baseline averaged over the treatment period. The results of this multicentre, 
double-blind, randomised trial showed that tacrolimus ointment, 0.03% and 0.1%, is significantly 
more effective (p<0.001 for both) than 1% hydrocortisone acetate ointment (Table 2). 
 
Table 2: Efficacy at week 3 
 
 

Hydrocortisone 
acetate 1% 
(N=185) 

Tacrolimus 0.03% 
(N=189) 

Tacrolimus 0.1% 
(N=186) 

Median mEASI as Percentage of 
Baseline mean AUC (Primary  
Endpoint)§  

64.0% 44.8% 39.8% 

Improvement ≥ 90% in Physician’s 
Global Evaluation 

15.7% 38.5% 48.4% 

§ lower values = greater improvement 
 
The incidence of local skin burning was higher in the tacrolimus treatment groups than in the 
hydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in the 
hydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signs 
in either treatment group throughout the clinical trial. 
 
The purpose of the third multicentre, double-blind, randomised study was the assessment of efficacy 
and safety of 0.03% tacrolimus ointment applied once or twice a day relative to twice daily 
administration of 1% hydrocortisone acetate ointment in children with moderate to severe atopic 
dermatitis. Treatment duration was for up to three weeks. 
 
Table 3: Efficacy at week 3 
 
 

Hydrocortisone 
acetate 1% 
Twice daily (N=207) 

Tacrolimus 0.03% 
Once daily (N=207) 

Tacrolimus 0.03% 
Twice daily (N=210) 

Median mEASI Percentage 47.2% 70.0% 78.7% 



21 

Decrease (Primary Endpoint)§ 
Improvement ≥90% in 
Physician’s Global Evaluation 

13.6% 27.8% 36.7% 

§ higher values = greater improvement 
 
The primary endpoint was defined as the percentage decrease in mEASI from the baseline to end of 
treatment. A statistically significant better improvement was shown for once daily and twice daily 
0.03% tacrolimus ointment compared to twice daily hydrocortisone acetate ointment (p<0.001 for 
both). Twice daily treatment with 0.03% tacrolimus ointment was more effective than once daily 
administration (Table 3). The incidence of local skin burning was higher in the tacrolimus treatment 
groups than in the hydrocortisone group. There were no clinically relevant changes in the laboratory 
values or vital signs in either treatment group throughout the study. 
 
In the fourth trial, approximately 800 patients (aged ≥2 years) received 0.1% tacrolimus ointment 
intermittently or continuously in an open-label, long-term safety study for up to four years, with 300 
patients receiving treatment for at least three years and 79 patients receiving treatment for a minimum 
of 42 months. Based on changes from baseline in EASI score and body surface area affected, patients 
regardless of age had improvement in their atopic dermatitis at all subsequent time points. In addition, 
there was no evidence of loss of efficacy throughout the duration of the clinical trial. The overall 
incidence of adverse events tended to decrease as the study progressed for all patients independent of 
age. The three most common adverse events reported were flu-like symptoms (cold, common cold, 
influenza, upper respiratory infection, etc.), pruritus and skin burning. No adverse events previously 
unreported in shorter duration and/or previous studies were observed in this long-term study. 
 
The efficacy and safety of tacrolimus ointment in maintenance treatment of mild to severe atopic 
dermatitis was assessed in 524 patients in two Phase III multicentre clinical trials of similar design, 
one in adult patients (≥16 years) and one in paediatric patients (2-15 years). In both studies, patients 
with active disease entered an open-label period (OLP) during which they treated affected lesions with 
tacrolimus ointment twice daily until improvement had reached a predefined score (Investigator’s 
Global Assessment [IGA] ≤ 2, i.e. clear, almost clear or mild disease) for a maximum of 6 weeks. 
Thereafter, patients entered a double-blind disease control period (DCP) for up to 12 months. Patients 
were randomised to receive either tacrolimus ointment (0.1% adults; 0.03% children) or vehicle, once 
a day twice weekly on Mondays and Thursdays. If a disease exacerbation occurred, patients were 
treated with open-label tacrolimus ointment twice daily for a maximum of 6 weeks until the IGA score 
returned to ≤2. 
The primary endpoint in both studies was the number of disease exacerbations requiring a “substantial 
therapeutic intervention” during the DCP, defined as an exacerbation with an IGA of 3-5 (i.e. 
moderate, severe and very severe disease) on the first day of the flare, and requiring more than 7 days 
treatment. Both studies showed significant benefit with twice weekly treatment with tacrolimus 
ointment with regard to the primary and key secondary endpoints over a period of 12 months in a 
pooled population of patients with mild to severe atopic dermatitis. In a subanalysis of a pooled 
population of patients with moderate to severe atopic dermatitis these differences remained 
statistically significant (Table 4). No adverse events not reported previously were observed in these 
studies. 
 
Table 4: Efficacy (moderate to severe subpopulation) 

 
 

Adults, ≥16 years Children, 2-15 years 
Tacrolimus 0.1% 
Twice weekly 
(N=80) 

Vehicle 
Twice weekly 
(N=73) 

Tacrolimus 
0.03% 
Twice weekly 
(N=78) 

Vehicle 
Twice weekly 
(N=75) 

Median number of DEs 
requiring substantial 
intervention adjusted for 
time at risk (% of patients 
without DE requiring 
substantial intervention)  

 
1.0 (48.8%) 

 
5.3 (17.8%) 

 
1.0 (46.2%) 

 
2.9 (21.3%) 



22 

Median time to first DE 
requiring substantial 
intervention 

142 days 15 days 217 days 36 days 

Median number of DEs 
adjusted for time at risk 
(% of patients without any 
DE periods) 

 
1.0 (42.5%) 

 
6.8 (12.3%) 

 
1.5 (41.0%) 

 
3.5 (14.7%) 

Median time to first DE  123 days 14 days 146 days 17 days 
Mean (SD) percentage of 
days of DE exacerbation 
treatment 

16.1 (23.6) 39.0 (27.8) 16.9 (22.1) 29.9 (26.8) 

DE: disease exacerbation 
P<0.001 in favour of tacrolimus ointment 0.1% (adults) and 0.03% (children) for the primary and key 
secondary endpoints  
 
A seven-month, double blind, randomised parallel group study of paediatric patients (2-11 years) with 
moderate to severe atopic dermatitis was performed. In one arm patients received Protopic 0.03% 
ointment (n=121) twice a day for 3 weeks and thereafter once a day until clearance. In the comparator 
arm patients received 1% hydrocortisone acetate ointment (HA) for head and neck and 0.1% 
hydrocortisone butyrate ointment for trunk and limbs (n=111) twice a day for 2 weeks and 
subsequently HA twice a day to all affected areas. During this period all patients and control subjects 
(n=44) received a primary immunisation and a rechallenge with a protein-conjugate vaccine against 
Neisseria menigitidis serogroup C. 
The primary endpoint of this study was the response rate to vaccination, defined as the percentage of 
patients with a serum bactericidal antibody (SBA) titre ≥ 8 at the week 5 visit. Analysis of the 
response rate at week 5 showed equivalence between the treatment groups (hydrocortisone 98.3%, 
tacrolimus ointment 95.4%; 7-11 years: 100% in both arms). The results in the control group were 
similar. 
The primary response to vaccination was not affected. 
 
5.2 Pharmacokinetic properties 
 
Clinical data have shown that tacrolimus concentrations in systemic circulation after topical 
administration are low and, when measurable, transient. 
 
Absorption 
Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimus 
following single or repeated topical application of tacrolimus ointment. 
Most atopic dermatitis patients (adults and children) treated with single or repeated application of 
tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated with tacrolimus ointment 
(0.03%) had blood concentrations < 1.0 ng/ml. When observed, blood concentrations exceeding 
1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. However, both 
the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and 
children with an average of 50% body surface area treated, systemic exposure (i.e. AUC) of tacrolimus 
from Protopic is approximately 30-fold less than that seen with oral immunosuppressive doses in 
kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic 
effects can be observed is not known.  
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated 
for prolonged periods (up to one year) with tacrolimus ointment.  
 
Distribution 
As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to 
plasma proteins is considered not to be clinically relevant. 
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skin 
with minimal diffusion into the systemic circulation. 
 
Biotransformation 



23 

Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus is 
extensively metabolised in the liver via CYP3A4. 
 
Elimination 
When administered intravenously, tacrolimus has been shown to have a low clearance rate. The 
average total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically available 
tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-
treated with drugs that are potent inhibitors of CYP3A4. 
Following repeated topical application of the ointment the average half-life of tacrolimus was 
estimated to be 75 hours for adults and 65 hours for children. 
 
Paediatric population 
The pharmacokinetics of tacrolimus after topical application are similar to those reported in adults, 
with minimal systemic exposure and no evidence of accumulation (see above). 
 
5.3 Preclinical safety data 
 
Repeated dose toxicity and local tolerance 
Repeated topical administration of tacrolimus ointment or the ointment vehicle to rats, rabbits and 
micropigs was associated with slight dermal changes such as erythema, oedema and papules.  
Long-term topical treatment of rats with tacrolimus led to systemic toxicity including alterations of 
kidneys, pancreas, eyes and nervous system. The changes were caused by high systemic exposure of 
rodents resulting from high transdermal absorption of tacrolimus. Slightly lower body weight gain in 
females was the only systemic change observed in micropigs at high ointment concentrations (3%). 
Rabbits were shown to be especially sensitive to intravenous administration of tacrolimus, reversible 
cardiotoxic effects being observed. 
 
Mutagenicity 
In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus. 
 
Carcinogenicity 
Systemic carcinogenicity studies in mice (18 months) and rats (24 months) revealed no carcinogenic 
potential of tacrolimus.  
In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumours 
were observed. In the same study an increased incidence of lymphoma was detected in association 
with high systemic exposure. 
In a photocarcinogenicity study, albino hairless mice were chronically treated with tacrolimus 
ointment and UV radiation. Animals treated with tacrolimus ointment showed a statistically significant 
reduction in time to skin tumour (squamous cell carcinoma) development and an increase in the 
number of tumours. It is unclear whether the effect of tacrolimus is due to systemic 
immunosuppression or a local effect. The risk for humans cannot be completely ruled out as the 
potential for local immunosuppression with the long-term use of tacrolimus ointment is unknown.  
 
Reproduction toxicity 
Embryo/foetal toxicity was observed in rats and rabbits, but only at doses that caused significant 
toxicity in maternal animals. Reduced sperm function was noted in male rats at high subcutaneous 
doses of tacrolimus. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
White soft paraffin 
Liquid paraffin 
Propylene carbonate 
White beeswax 



24 

Hard paraffin 
Butylhydroxytoluene (E321) 
All-rac-α-tocopherol 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
 
6.5 Nature and contents of container 
 
Laminate tube with an inner lining of low-density-polyethylene fitted with a white polypropylene 
screw cap. 
 
Package sizes: 10 g, 30 g and 60 g. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/201/003 
EU/1/02/201/004 
EU/1/02/201/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 28 February 2002 
Date of latest renewal: 20 November 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 



25 

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu/


26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



27 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Astellas Ireland Co. Ltd. 
Killorglin 
County Kerry 
Ireland 
 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRUCTIONS WITH REGARD TO THE SAFE AND EFECTIVE 

USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk 
profile or as the result of an important (pharmacovigilance or risk minimisation) 
milestone being reached. 

 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



30 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
PROTOPIC 0.03% OINTMENT (10 g, 30 g, 60 g CARTON) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Protopic 0.03% ointment 
tacrolimus monohydrate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
1 g ointment contains: 0.3 mg tacrolimus (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, 
butylhydroxytoluene (E321), all-rac-α-tocopherol. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Ointment 
 
10 g 
30 g 
60 g 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Cutaneous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 



31 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/201/005 10 g 
EU/1/02/201/001 30 g 
EU/1/02/201/002 60 g 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Protopic 0.03% 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



32 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PROTOPIC 0.03% OINTMENT (10 g TUBE)  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Protopic 0.03% ointment 
tacrolimus monohydrate 
Cutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 g 
 
 
6. OTHER 
 
Keep out of the sight and reach of children. 
 
Do not store above 25°C. 
 
EU/1/02/201/005 
 
 



33 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
PROTOPIC 0.03% OINTMENT (30 g, 60 g TUBE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Protopic 0.03% ointment 
tacrolimus monohydrate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
1 g ointment contains: 0.3 mg tacrolimus (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, 
butylhydroxytoluene (E321), all-rac-α-tocopherol. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Ointment 
 
30 g 
60 g 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Cutaneous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
 



34 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/201/001 30 g 
EU/1/02/201/002 60 g 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



35 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
PROTOPIC 0.1% OINTMENT (10 g, 30 g, 60 g CARTON) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Protopic 0.1% ointment 
tacrolimus monohydrate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
1 g ointment contains: 1.0 mg tacrolimus (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, 
butylhydroxytoluene (E321), all-rac-α-tocopherol. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Ointment 
 
10 g 
30 g 
60 g 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Cutaneous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 



36 

 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/201/006 10 g 
EU/1/02/201/003 30 g 
EU/1/02/201/004 60 g 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Protopic 0.1% 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



37 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PROTOPIC 0.1% OINTMENT (10 g TUBE)  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Protopic 0.1% ointment 
tacrolimus monohydrate 
Cutaneous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
10 g 
 
 
6. OTHER 
 
Keep out of the sight and reach of children. 
 
Do not store above 25°C. 
 
EU/1/02/201/006 
 
 



38 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
PROTOPIC 0.1% OINTMENT (30 g, 60 g TUBE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Protopic 0.1% ointment 
tacrolimus monohydrate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
1 g ointment contains: 1.0 mg tacrolimus (as monohydrate) 
 
 
3. LIST OF EXCIPIENTS 
 
white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, 
butylhydroxytoluene (E321), all-rac-α-tocopherol. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Ointment 
 
30 g 
60 g 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Cutaneous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
 



39 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS 
 
EU/1/02/201/003 30 g 
EU/1/02/201/004 60 g 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



41 

Package leaflet: Information for the user 
 

Protopic 0.03% ointment 
tacrolimus monohydrate 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Protopic is and what it is used for 
2. What you need to know before you use Protopic 
3. How to use Protopic 
4. Possible side effects 
5. How to store Protopic 
6. Contents of the pack and other information 
 
 
1. What Protopic is and what it is used for 
 
The active substance of Protopic, tacrolimus monohydrate, is an immunomodulating agent.  
 
Protopic 0.03% ointment is used to treat moderate to severe atopic dermatitis (eczema) in adults who 
are not adequately responsive to or are intolerant of conventional therapies such as topical 
corticosteroids and in children (2 years of age and older) who failed to respond adequately to 
conventional therapies such as topical corticosteroids.  
 
Once moderate to severe atopic dermatitis is cleared or almost cleared after up to 6 weeks treatment of 
a flare, and if you are experiencing frequent flares (i.e. 4 or more per year), it may be possible to 
prevent flares coming back or prolong the time you are free from flares by using Protopic 0.03% 
ointment twice weekly. 
 
In atopic dermatitis, an over-reaction of the skin’s immune system causes skin inflammation 
(itchiness, redness, dryness). Protopic alters the abnormal immune response and relieves the skin 
inflammation and the itch. 
 
 
2. What you need to know before you use Protopic  
 
Do not use Protopic 
• If you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 

6) or to macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin). 
 
Warnings and precautions 
Talk to your doctor before using Protopic: 
• If you have liver failure. 
• If you have any skin malignancies (tumours) or if you have a weakened immune system 

(immuno-compromised) whatever the cause. 
• If you have an inherited skin barrier disease such as Netherton’s syndrome, lamellar 

ichthyosis (extensive scaling of the skin due to a thickening of the outer layer of the skin), or if 



42 

you suffer from generalised erythroderma (inflammatory reddening and scaling of the entire 
skin). 

• If you have a cutaneous Graft Versus Host Disease (an immune reaction of the skin which is a 
common complication in patients who have undergone a bone marrow transplant). 

• If you have swollen lymph nodes at initiation of treatment. If your lymph nodes become 
swollen during treatment with Protopic, consult your doctor. 

• If you have infected lesions. Do not apply the ointment to infected lesions. 
• If you notice any change to the appearance of your skin, please inform your physician. 
 
• The safety of using Protopic for a long time is not known. A very small number of people who 

have used Protopic ointment have had malignancies (for example, skin or lymphoma). However, 
a link to Protopic ointment treatment has not been shown. 

• Avoid exposing the skin to long periods of sunlight or artificial sunlight such as tanning beds. If 
you spend time outdoors after applying Protopic, use a sunscreen and wear loose fitting clothing 
that protects the skin from the sun. In addition, ask your doctor for advice on other appropriate 
sun protection methods. If you are prescribed light therapy, inform your doctor that you are 
using Protopic as it is not recommended to use Protopic and light therapy at the same time. 

• If your doctor tells you to use Protopic twice weekly to keep your atopic dermatitis cleared, 
your condition should be reviewed by your doctor at least every 12 months, even if it remains 
under control. In children, maintenance treatment should be suspended after 12 months, to 
assess whether the need for continued treatment still exists. 

 
Children 
• Protopic ointment is not approved for children younger than 2 years of age. Therefore it 

should not be used in this age group. Please consult your doctor. 
• The effect of treatment with Protopic on the developing immune system in children, especially 

the young, has not been established. 
 
Other medicines, cosmetics and Protopic 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
You may use moisturising creams and lotions during treatment with Protopic but these products 
should not be used within two hours of applying Protopic. 
 
The use of Protopic at the same time as other preparations to be used on the skin or while taking oral 
corticosteroids (e.g. cortisone) or medicines which affect the immune system has not been studied. 
 
Protopic with alcohol 
While using Protopic, drinking alcohol may cause the skin or face to become flushed or red and feel 
hot. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Protopic contains butylhydroxytoluene (E321) 
Protopic contains butylhydroxytoluene (E321), which may cause local skin reactions (e.g. contact 
dermatitis), or irritation to the eyes and mucous membranes. 
 
 
3. How to use Protopic  
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.  
 
• Apply Protopic as a thin layer to affected areas of your skin. 



43 

• Protopic may be used on most parts of the body, including the face and neck and in the creases 
of your elbows and knees. 

• Avoid using the ointment inside your nose or mouth or in your eyes. If the ointment gets on any 
of these areas, it should be thoroughly wiped off and/or rinsed off with water. 

• Do not cover the skin being treated with bandages or wraps. 
• Wash your hands after applying Protopic unless your hands are also being treated. 
• Before applying Protopic after a bath or shower, be sure your skin is completely dry. 
 
Children (2 years of age and older) 
Apply Protopic 0.03 % ointment twice a day for up to three weeks, once in the morning and once in 
the evening. Afterwards the ointment should be used once a day on each affected region of the skin 
until the eczema has gone away. 
 
Adults (16 years of age and older) 
Two strengths of Protopic (Protopic 0.03% and Protopic 0.1% ointment) are available for adult 
patients (16 years of age and older). Your doctor will decide which strength is best for you.  
 
Usually, treatment is started with Protopic 0.1% ointment twice a day, once in the morning and once in 
the evening, until the eczema has cleared. Depending on the response of your eczema your doctor will 
decide if the frequency of application can be reduced or the lower strength, Protopic 0.03% ointment, 
can be used. 
 
Treat each affected region of your skin until the eczema has gone away. Improvement is usually seen 
within one week. If you do not see any improvement after two weeks, see your doctor about other 
possible treatments.  
 
You may be told by your doctor to use Protopic ointment twice weekly once your atopic dermatitis has 
cleared or almost cleared (Protopic 0.03% for children and Protopic 0.1% for adults). Protopic 
ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas of your 
body commonly affected by atopic dermatitis. There should be 2–3 days without Protopic treatment 
between applications. 
If symptoms reappear you should use Protopic twice daily as outlined above and arrange to see your 
doctor to review your treatment. 
 
If you accidentally swallow some ointment 
If you accidentally swallow the ointment, consult your doctor or pharmacist as soon as possible. Do 
not try to induce vomiting. 
 
If you forget to use Protopic 
If you forget to apply the ointment at the scheduled time, do it as soon as you remember and then 
continue as before. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Very common (may affect more than 1 in 10 people): 
• burning sensation and itching  
These symptoms are usually mild to moderate and generally go away within one week of using 
Protopic.  
 
Common (may affect up to 1 in 10 people): 
• redness 
• feeling of warmth 



44 

• pain  
• increased skin sensitivity (especially to hot and cold) 
• skin tingling 
• rash 
• local skin infection regardless of specific cause including but not limited to: inflamed or 

infected hair follicles, cold sores, generalised herpes simplex infections 
• facial flushing or skin irritation after drinking alcohol is also common  
 
Uncommon (may affect fewer than 1 in 100 people): 
• acne  
 
Following twice-weekly treatment application site infections have been reported in children and adults. 
Impetigo, a superficial bacterial skin infection that usually produces blisters or sores on skin, has been 
reported in children. 
 
Rosacea (facial redness), rosacea-like dermatitis, lentigo (presence of flat brown spots on the skin), 
oedema at the application site and herpes eye infections have been reported during post-marketing 
experience. 
 
Since commercial availability a very small number of people who have used Protopic ointment have 
had malignancies (for example lymphoma, including skin lymphoma, and other skin tumours). 
However, a link to Protopic ointment treatment has not been confirmed or refuted on the available 
evidence so far. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Protopic 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the tube and carton after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 25ºC. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information  
 
What Protopic contains 
• The active substance is tacrolimus monohydrate. 

One gram of Protopic 0.03% ointment contains 0.3 mg tacrolimus (as tacrolimus monohydrate). 
• The other ingredients are white soft paraffin, liquid paraffin, propylene carbonate, white 

beeswax, hard paraffin, butylhydroxytoluene (E321) and all-rac-α-tocopherol. 
 
What Protopic looks like and contents of the pack  
Protopic is a white to slightly yellowish ointment. It is supplied in tubes containing 10, 30 or 60 grams 
of ointment. Not all pack sizes may be marketed. Protopic is available in two strengths (Protopic 
0.03% and Protopic 0.1% ointment). 
 
Marketing Authorisation Holder 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45 

LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
Manufacturer  
Astellas Ireland Co. Ltd. 
Killorglin 
County Kerry 
Ireland 
 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12  
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Lietuva 
Biocodex UAB 
Tel: +370 37 408 681 
 

България 
Borola Ltd 
Teл.: +359 2 9156 136 
 

Luxembourg/Luxemburg 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Česká republika 
LEO Pharma s.r.o. 
Tel: +420 225 992 272  
 

Magyarország 
LEO Pharma  
Tel: +36 1 888 0525 
 

Danmark 
LEO Pharma AB 
Tlf: +45 70 22 49 11  
 

Malta 
E.J. Busuttil Ltd 
Tel: +356 2144 7184 
 

Deutschland 
LEO Pharma GmbH 
Tel: +49 6102 2010 
 

Nederland 
LEO Pharma B.V.   
Tel: +31 205104141 
 

Eesti  
Biocodex OÜ 
Tel: +372 6 056 014 

Norge 
LEO Pharma AS 
Tlf: +47 22514900 
 

Ελλάδα 
LEO Pharmaceutical Hellas S.A. 
Τηλ: +30 210 68 34322 
 

Österreich 
LEO Pharma GmbH 
Tel: +43 1 503 6979 
 

España 
Laboratorios LEO Pharma, S.A. 
Tel: +34 93 221 3366 
 

Polska 
LEO Pharma Sp. z o.o. 
Tel: +48 22 244 18 40 
 

France 
Laboratoires LEO SA 
Tél: +33 1 3014 40 00 
 

Portugal 
LEO Farmacêuticos Lda.  
Tel: +351 21 711 0760 
 

tel:+37037408681


46 

Hrvatska 
Remedia d.o.o.                                                              
Tel:+385 1 3778 770 
 

România 
LEO Pharma A/S România 
Tel: +40 213121963 
 

Ireland 
LEO Laboratories Ltd 
Tel: +353 1 490 8924 
 

Slovenija 
PHARMAGAN d.o.o. 
Tel: +386 4 2366 700 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
LEO Pharma s.r.o. 
Tel: +421 2 5939 6236 
  

Italia 
LEO Pharma S.p.A.  
Tel: +39 06 52625500 
 

Suomi/Finland 
LEO Pharma Oy 
Puh./Tel: +358 20 721 8440 
 

Κύπρος 
The Star Medicines Importers Co. Ltd. 
Τηλ: +357 2537 1056  
 

Sverige 
LEO Pharma AB 
Tel: +46 40 3522 00  
 

Latvija 
Biocodex SIA 
Tel: +371 6761 9365 

United Kingdom 
LEO Laboratories Ltd 
Tel: +44 1844 347333 
 

 
This leaflet was last revised in. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu/


47 

Package leaflet: Information for the user 
 

Protopic 0.1% ointment 
tacrolimus monohydrate 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Protopic is and what it is used for 
2. What you need to know before you use Protopic 
3. How to use Protopic 
4. Possible side effects 
5. How to store Protopic 
6. Contents of the pack and other information 
 
 
1. What Protopic is and what it is used for 
 
The active substance of Protopic, tacrolimus monohydrate, is an immunomodulating agent.  
 
Protopic 0.1% ointment is used to treat moderate to severe atopic dermatitis (eczema) in adults who 
are not adequately responsive to or are intolerant of conventional therapies such as topical 
corticosteroids. 
 
Once moderate to severe atopic dermatitis is cleared or almost cleared after up to 6 weeks treatment of 
a flare, and if you are experiencing frequent flares (i.e. 4 or more per year), it may be possible to 
prevent flares coming back or prolong the time you are free from flares by using Protopic 0.1% 
ointment twice weekly. 
 
In atopic dermatitis, an over-reaction of the skin’s immune system causes skin inflammation 
(itchiness, redness, dryness). Protopic alters the abnormal immune response and relieves the skin 
inflammation and the itch. 
 
 
2. What you need to know before you use Protopic 
 
Do not use Protopic 
• If you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 

6) or to macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin). 
 
Warnings and precautions 
Talk to your doctor before using Protopic: 
• If you have liver failure. 
• If you have any skin malignancies (tumours) or if you have a weakened immune system 

(immuno-compromised) whatever the cause. 
• If you have an inherited skin barrier disease such as Netherton’s syndrome, lamellar 

ichthyosis (extensive scaling of the skin due to a thickening of the outer layer of the skin), or if 
you suffer from generalised erythroderma (inflammatory reddening and scaling of the entire 
skin).  



48 

• If you have a cutaneous Graft Versus Host Disease (an immune reaction of the skin which is a 
common complication in patients who have undergone a bone marrow transplant). 

• If you have swollen lymph nodes at initiation of treatment. If your lymph nodes become 
swollen during treatment with Protopic, consult your doctor 

• If you have infected lesions. Do not apply the ointment to infected lesions. 
• If you notice any change to the appearance of your skin, please inform your physician. 

 
• The safety of using Protopic for a long time is not known. A very small number of people who 

have used Protopic ointment have had malignancies (for example, skin or lymphoma). However, 
a link to Protopic ointment treatment has not been shown. 

• Avoid exposing the skin to long periods of sunlight or artificial sunlight such as tanning beds. If 
you spend time outdoors after applying Protopic, use a sunscreen and wear loose fitting clothing 
that protects the skin from the sun. In addition, ask your doctor for advice on other appropriate 
sun protection methods. If you are prescribed light therapy, inform your doctor that you are 
using Protopic as it is not recommended to use Protopic and light therapy at the same time. 

• If your doctor tells you to use Protopic twice weekly to keep your atopic dermatitis cleared, 
your condition should be reviewed by your doctor at least every 12 months, even if it remains 
under control. In children, maintenance treatment should be suspended after 12 months, to 
assess whether the need for continued treatment still exists. 

 
Children 
• Protopic 0.1 % ointment is not approved for children younger than 16 years of age. 

Therefore it should not be used in this age group. Please consult your doctor. 
• The effect of treatment with Protopic on the developing immune system in children, especially 

the young, has not been established. 
 
Other medicines, cosmetics and Protopic 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
You may use moisturising creams and lotions during treatment with Protopic but these products 
should not be used within two hours of applying Protopic. 
 
The use of Protopic at the same time as other preparations to be used on the skin or while taking oral 
corticosteroids (e.g. cortisone) or medicines which affect the immune system has not been studied. 
 
Protopic with alcohol 
While using Protopic, drinking alcohol may cause the skin or face to become flushed or red and feel 
hot. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Protopic contains butylhydroxytoluene (E321) 
Protopic contains butylhydroxytoluene (E321), which may cause local skin reactions (e.g. contact 
dermatitis), or irritation to the eyes and mucous membranes. 
 
 
3. How to use Protopic 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.  
 
• Apply Protopic as a thin layer to affected areas of your skin. 
• Protopic may be used on most parts of the body, including the face and neck and in the creases 

of your elbows and knees. 



49 

• Avoid using the ointment inside your nose or mouth or in your eyes. If the ointment gets on any 
of these areas, it should be thoroughly wiped off and/or rinsed off with water. 

• Do not cover the skin being treated with bandages or wraps. 
• Wash your hands after applying Protopic unless your hands are also being treated. 
• Before applying Protopic after a bath or shower, be sure your skin is completely dry. 
 
Adults (16 years of age and older) 
Two strengths of Protopic (Protopic 0.03% and Protopic 0.1% ointment) are available for adult 
patients (16 years of age and older). Your doctor will decide which strength is best for you.  
 
Usually, treatment is started with Protopic 0.1% ointment twice a day, once in the morning and once in 
the evening, until the eczema has cleared. Depending on the response of your eczema your doctor will 
decide if the frequency of application can be reduced or the lower strength, Protopic 0.03% ointment, 
can be used. 
 
Treat each affected region of your skin until the eczema has gone away. Improvement is usually seen 
within one week. If you do not see any improvement after two weeks, see your doctor about other 
possible treatments.  
 
You may be told by your doctor to use Protopic 0.1% ointment twice weekly once your atopic 
dermatitis has cleared or almost cleared. Protopic 0.1 % ointment should be applied once a day twice 
weekly (e.g. Monday and Thursday) to areas of your body commonly affected by atopic dermatitis. 
There should be 2–3 days without Protopic treatment between applications. 
If symptoms reappear you should use Protopic twice daily as outlined above and arrange to see your 
doctor to review your treatment. 
 
If you accidentally swallow some ointment 
If you accidentally swallow the ointment, consult your doctor or pharmacist as soon as possible. Do 
not try to induce vomiting. 
 
If you forget to use Protopic 
If you forget to apply the ointment at the scheduled time, do it as soon as you remember and then 
continue as before. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Very common (may affect more than 1 in 10 people): 
• burning sensation and itching  
These symptoms are usually mild to moderate and generally go away within one week of using 
Protopic.  
 
Common (may affect up to 1 in 10 people): 
• redness 
• feeling of warmth 
• pain  
• increased skin sensitivity (especially to hot and cold) 
• skin tingling 
• rash 
• local skin infection regardless of specific cause including but not limited to: inflamed or 

infected hair follicles, cold sores, generalised herpes simplex infections  
• facial flushing or skin irritation after drinking alcohol is also common  



50 

 
Uncommon (may affect fewer than 1 in 100 people): 
• acne 
Following twice-weekly treatment application site infections have been reported in adults.  
 
Rosacea (facial redness), rosacea-like dermatitis, lentigo (presence of flat brown spots on the skin), 
oedema at the application site and herpes eye infections have been reported during post-marketing 
experience. 
 
Since commercial availability a very small number of people who have used Protopic ointment have 
had malignancies (for example lymphoma, including skin lymphoma, and other skin tumours). 
However, a link to Protopic ointment treatment has not been confirmed or refuted on the available 
evidence so far. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Protopic 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the tube and carton after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 25ºC. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Protopic contains 
• The active substance is tacrolimus monohydrate. 

One gram of Protopic 0.1% ointment contains 1.0 mg tacrolimus (as tacrolimus monohydrate). 
• The other ingredients are white soft paraffin, liquid paraffin, propylene carbonate, white 

beeswax, hard paraffin, butylhydroxytoluene (E321) and all-rac-α-tocopherol. 
 
What Protopic looks like and contents of the pack  
Protopic is a white to slightly yellowish ointment. It is supplied in tubes containing 10, 30 or 60 grams 
of ointment. Not all pack sizes may be marketed. Protopic is available in two strengths (Protopic 
0.03% and Protopic 0.1% ointment). 
 
Marketing Authorisation Holder 
LEO Pharma A/S 
Industriparken 55 
2750 Ballerup 
Denmark 
 
Manufacturer 
Astellas Ireland Co. Ltd. 
Killorglin 
County Kerry 
Ireland 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


51 

 
LEO Laboratories Ltd. 
285 Cashel Road 
Crumlin, Dublin 12  
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Lietuva 
Biocodex UAB 
Tel: +370 37 408 681 

България 
Borola Ltd 
Teл.: +359 2 9156 136 
 

Luxembourg/Luxemburg 
LEO Pharma N.V./S.A 
Tél/Tel: +32 3 740 7868 
 

Česká republika 
LEO Pharma s.r.o. 
Tel: +420 225 992 272  
 

Magyarország 
LEO Pharma  
Tel: +36 1 888 0525 
 

Danmark 
LEO Pharma AB 
Tlf: +45 70 22 49 11  
 

Malta 
E.J. Busuttil Ltd 
Tel: +356 2144 7184 
 

Deutschland 
LEO Pharma GmbH 
Tel: +49 6102 2010 
 

Nederland 
LEO Pharma B.V.   
Tel: +31 205104141 
 

Eesti  
Biocodex OÜ 
Tel: +372 6 056 014 

Norge 
LEO Pharma AS 
Tlf: +47 22514900 
 

Ελλάδα 
LEO Pharmaceutical Hellas S.A. 
Τηλ: +30 210 68 34322 
 

Österreich 
LEO Pharma GmbH 
Tel: +43 1 503 6979 
 

España 
Laboratorios LEO Pharma, S.A. 
Tel: +34 93 221 3366 
 

Polska 
LEO Pharma Sp. z o.o. 
Tel: +48 22 244 18 40 
 

France 
Laboratoires LEO SA 
Tél: +33 1 3014 40 00 
 

Portugal 
LEO Farmacêuticos Lda.  
Tel: +351 21 711 0760 
 

Hrvatska 
Remedia d.o.o.                                                              
Tel:+385 1 3778 770 
 

România 
LEO Pharma A/S România 
Tel: +40 213121963 
 

Ireland 
LEO Laboratories Ltd 
Tel: +353 1 490 8924 
 

Slovenija 
PHARMAGAN d.o.o. 
Tel: +386 4 2366 700 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
LEO Pharma s.r.o. 
Tel: +421 2 5939 6236 
  



52 

Italia 
LEO Pharma S.p.A.  
Tel: +39 06 52625500 
 

Suomi/Finland 
LEO Pharma Oy 
Puh./Tel: +358 20 721 8440 
 

Κύπρος 
The Star Medicines Importers Co. Ltd. 
Τηλ: +357 2537 1056  
 

Sverige 
LEO Pharma AB 
Tel: +46 40 3522 00  
 

Latvija 
Biocodex SIA 
Tel: +371 6761 9365 

United Kingdom 
LEO Laboratories Ltd 
Tel: +44 1844 347333 
 

 
This leaflet was last revised in. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRUCTIONS WITH REGARD TO THE SAFE AND EFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
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{'Title': '2. what you need to know before you use protopic', 'Section_Content': "do not use protopic if you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 6) or to macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin). warnings and precautions talk to your doctor before using protopic: if you have liver failure. if you have any skin malignancies (tumours) or if you have a weakened immune system (immuno-compromised) whatever the cause. if you have an inherited skin barrier disease such as netherton's syndrome, lamellar ichthyosis (extensive scaling of the skin due to a thickening of the outer layer of the skin), or if 42 you suffer from generalised erythroderma (inflammatory reddening and scaling of the entire skin). if you have a cutaneous graft versus host disease (an immune reaction of the skin which is a common complication in patients who have undergone a bone marrow transplant). if you have swollen lymph nodes at initiation of treatment. if your lymph nodes become swollen during treatment with protopic, consult your doctor. if you have infected lesions. do not apply the ointment to infected lesions. if you notice any change to the appearance of your skin, please inform your physician. the safety of using protopic for a long time is not known. a very small number of people who have used protopic ointment have had malignancies (for example, skin or lymphoma). however, a link to protopic ointment treatment has not been shown. avoid exposing the skin to long periods of sunlight or artificial sunlight such as tanning beds. if you spend time outdoors after applying protopic, use a sunscreen and wear loose fitting clothing that protects the skin from the sun. in addition, ask your doctor for advice on other appropriate sun protection methods. if you are prescribed light therapy, inform your doctor that you are using protopic as it is not recommended to use protopic and light therapy at the same time. if your doctor tells you to use protopic twice weekly to keep your atopic dermatitis cleared, your condition should be reviewed by your doctor at least every 12 months, even if it remains under control. in children, maintenance treatment should be suspended after 12 months, to assess whether the need for continued treatment still exists. children protopic ointment is not approved for children younger than 2 years of age. therefore it should not be used in this age group. please consult your doctor. the effect of treatment with protopic on the developing immune system in children, especially the young, has not been established. other medicines, cosmetics and protopic tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. you may use moisturising creams and lotions during treatment with protopic but these products should not be used within two hours of applying protopic. the use of protopic at the same time as other preparations to be used on the skin or while taking oral corticosteroids (e.g. cortisone) or medicines which affect the immune system has not been studied. protopic with alcohol while using protopic, drinking alcohol may cause the skin or face to become flushed or red and feel hot. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. protopic contains butylhydroxytoluene (e321) protopic contains butylhydroxytoluene (e321), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.", 'Entity_Recognition': [{'Text': 'protopic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 16, 'BeginOffset': 11, 'EndOffset': 19, 'Score': 0.9969966411590576, 'Text': 'protopic', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.6691612005233765}]}, {'Text': 'allergic', 'Type': 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{'Title': '3. how to use protopic', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. apply protopic as a thin layer to affected areas of your skin. protopic may be used on most parts of the body, including the face and neck and in the creases of your elbows and knees. avoid using the ointment inside your nose or mouth or in your eyes. if the ointment gets on any of these areas, it should be thoroughly wiped off and/or rinsed off with water. do not cover the skin being treated with bandages or wraps. wash your hands after applying protopic unless your hands are also being treated. before applying protopic after a bath or shower, be sure your skin is completely dry. children (2 years of age and older) apply protopic 0.03 % ointment twice a day for up to three weeks, once in the morning and once in the evening. afterwards the ointment should be used once a day on each affected region of the skin until the eczema has gone away. adults (16 years of age and older) two strengths of protopic (protopic 0.03% and protopic 0.1% ointment) are available for adult patients (16 years of age and older). your doctor will decide which strength is best for you. usually, treatment is started with protopic 0.1% ointment twice a day, once in the morning and once in the evening, until the eczema has cleared. depending on the response of your eczema your doctor will decide if the frequency of application can be reduced or the lower strength, protopic 0.03% ointment, can be used. treat each affected region of your skin until the eczema has gone away. improvement is usually seen within one week. if you do not see any improvement after two weeks, see your doctor about other possible treatments. you may be told by your doctor to use protopic ointment twice weekly once your atopic dermatitis has cleared or almost cleared (protopic 0.03% for children and protopic 0.1% for adults). protopic ointment should be applied once a day twice weekly (e.g. monday and thursday) to areas of your body commonly affected by atopic dermatitis. there should be 23 days without protopic treatment between applications. if symptoms reappear you should use protopic twice daily as outlined above and arrange to see your doctor to review your treatment. if you accidentally swallow some ointment if you accidentally swallow the ointment, consult your doctor or pharmacist as soon as possible. do not try to induce vomiting. if you forget to use protopic if you forget to apply the ointment at the scheduled time, do it as soon as you remember and then continue as before. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'protopic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Id': 16, 'BeginOffset': 126, 'EndOffset': 134, 'Score': 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. very common (may affect more than 1 in 10 people): burning sensation and itching these symptoms are usually mild to moderate and generally go away within one week of using protopic. common (may affect up to 1 in 10 people): redness feeling of warmth 44 pain increased skin sensitivity (especially to hot and cold) skin tingling rash local skin infection regardless of specific cause including but not limited to: inflamed or infected hair follicles, cold sores, generalised herpes simplex infections facial flushing or skin irritation after drinking alcohol is also common uncommon (may affect fewer than 1 in 100 people): acne following twice-weekly treatment application site infections have been reported in children and adults. impetigo, a superficial bacterial skin infection that usually produces blisters or sores on skin, has been reported in children. rosacea (facial redness), rosacea-like dermatitis, lentigo (presence of flat brown spots on the skin), oedema at the application site and herpes eye infections have been reported during post-marketing experience. since commercial availability a very small number of people who have used protopic ointment have had malignancies (for example lymphoma, including skin lymphoma, and other skin tumours). however, a link to protopic ointment treatment has not been confirmed or refuted on the available evidence so far. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'protopic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all 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[]}]}, {'Id': 9, 'BeginOffset': 1070, 'EndOffset': 1086, 'Score': 0.898578941822052, 'Text': 'application site', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 52, 'BeginOffset': 1091, 'EndOffset': 1112, 'Score': 0.5917014479637146, 'Text': 'herpes eye infections', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9445789456367493}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9770001173019409, 'RelationshipScore': 0.5530668497085571, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 10, 'BeginOffset': 1098, 'EndOffset': 1101, 'Text': 'eye', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 10, 'BeginOffset': 1098, 'EndOffset': 1101, 'Score': 0.9770001173019409, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'protopic ointment', 'Type': 'TREATMENT', 'BeginOffset': 1240, 'EndOffset': 1257}, {'Id': 53, 'BeginOffset': 1267, 'EndOffset': 1279, 'Score': 0.9405798316001892, 'Text': 'malignancies', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9439835548400879}]}, {'Text': 'example lymphoma', 'Type': 'PROBLEM', 'BeginOffset': 1285, 'EndOffset': 1301}, {'Id': 55, 'BeginOffset': 1313, 'EndOffset': 1326, 'Score': 0.9042531251907349, 'Text': 'skin lymphoma', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.966582179069519}]}, {'Text': 'other skin tumours', 'Type': 'PROBLEM', 'BeginOffset': 1332, 'EndOffset': 1350}, {'Text': 'protopic ointment treatment', 'Type': 'TREATMENT', 'BeginOffset': 1372, 'EndOffset': 1399}, {'Id': 57, 'BeginOffset': 1481, 'EndOffset': 1493, 'Score': 0.937776505947113, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6392505168914795}]}, {'Id': 58, 'BeginOffset': 1509, 'EndOffset': 1521, 'Score': 0.9139950275421143, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6915079355239868}]}, {'Id': 59, 'BeginOffset': 1585, 'EndOffset': 1597, 'Score': 0.9531046152114868, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5961185097694397}, {'Name': 'DIAGNOSIS', 'Score': 0.4228479862213135}]}, {'Id': 60, 'BeginOffset': 1646, 'EndOffset': 1658, 'Score': 0.857890248298645, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6782200932502747}]}, {'Id': 61, 'BeginOffset': 1712, 'EndOffset': 1723, 'Score': 0.3812955319881439, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5823803544044495}, {'Name': 'DIAGNOSIS', 'Score': 0.41077059507369995}]}, {'Id': 62, 'BeginOffset': 1737, 'EndOffset': 1749, 'Score': 0.8612218499183655, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7235421538352966}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1805, 'EndOffset': 1818}]}
{'Title': '5. how to store protopic', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the tube and carton after exp. the expiry date refers to the last day of that month. do not store above 25ºc. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what protopic contains the active substance is tacrolimus monohydrate. one gram of protopic 0.03% ointment contains 0.3 mg tacrolimus (as tacrolimus monohydrate). the other ingredients are white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, butylhydroxytoluene (e321) and all-rac-α-tocopherol. what protopic looks like and contents of the pack protopic is a white to slightly yellowish ointment. it is supplied in tubes containing 10, 30 or 60 grams of ointment. not all pack sizes may be marketed. protopic is available in two strengths (protopic 0.03% and protopic 0.1% ointment).', 'Entity_Recognition': [{'Text': 'protopic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.9892427325248718, 'Text': 'protopic', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 47, 'EndOffset': 69, 'Score': 0.9340577125549316, 'Text': 'tacrolimus monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.9978458881378174, 'RelationshipScore': 0.9117637872695923, 'RelationshipType': 'STRENGTH', 'Id': 4, 'BeginOffset': 92, 'EndOffset': 97, 'Text': '0.03%', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9851109385490417, 'RelationshipScore': 0.9364571571350098, 'RelationshipType': 'FORM', 'Id': 5, 'BeginOffset': 98, 'EndOffset': 106, 'Text': 'ointment', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 3, 'BeginOffset': 83, 'EndOffset': 91, 'Score': 0.9987114667892456, 'Text': 'protopic', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9569445252418518, 'RelationshipScore': 0.9988896250724792, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 71, 'EndOffset': 79, 'Text': 'one gram', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'STRENGTH', 'Score': 0.9978458881378174, 'RelationshipScore': 0.9999850988388062, 'RelationshipType': 'STRENGTH', 'Id': 4, 'BeginOffset': 92, 'EndOffset': 97, 'Text': '0.03%', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9851109385490417, 'RelationshipScore': 0.9999743700027466, 'RelationshipType': 'FORM', 'Id': 5, 'BeginOffset': 98, 'EndOffset': 106, 'Text': 'ointment', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.7954409122467041, 'RelationshipScore': 0.7350735664367676, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 116, 'EndOffset': 122, 'Text': '0.3 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '0.03', 'Type': 'NUMBER', 'BeginOffset': 92, 'EndOffset': 96}, {'Text': '0.3', 'Type': 'NUMBER', 'BeginOffset': 116, 'EndOffset': 119}, {'Id': 7, 'BeginOffset': 123, 'EndOffset': 133, 'Score': 0.997461199760437, 'Text': 'tacrolimus', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9569445252418518, 'RelationshipScore': 0.9882771372795105, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 71, 'EndOffset': 79, 'Text': 'one gram', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.7954409122467041, 'RelationshipScore': 0.9998239874839783, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 116, 'EndOffset': 122, 'Text': '0.3 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'tacrolimus monohydrate)', 'Type': 'TREATMENT', 'BeginOffset': 138, 'EndOffset': 161}, {'Text': 'white soft paraffin', 'Type': 'TREATMENT', 'BeginOffset': 189, 'EndOffset': 208}, {'Text': 'liquid paraffin', 'Type': 'TREATMENT', 'BeginOffset': 210, 'EndOffset': 225}, {'Id': 11, 'BeginOffset': 227, 'EndOffset': 246, 'Score': 0.9971699118614197, 'Text': 'propylene carbonate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 248, 'EndOffset': 261, 'Score': 0.5369282364845276, 'Text': 'white beeswax', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'hard paraffin', 'Type': 'TREATMENT', 'BeginOffset': 263, 'EndOffset': 276}, {'Id': 13, 'BeginOffset': 278, 'EndOffset': 297, 'Score': 0.985822856426239, 'Text': 'butylhydroxytoluene', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 313, 'EndOffset': 329, 'Score': 0.8343697786331177, 'Text': 'rac-α-tocopherol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 336, 'EndOffset': 344, 'Score': 0.9935196042060852, 'Text': 'protopic', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'the pack protopic', 'Type': 'TREATMENT', 'BeginOffset': 372, 'EndOffset': 389}, {'Text': 'a white to slightly yellowish ointment', 'Type': 'PROBLEM', 'BeginOffset': 393, 'EndOffset': 431}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 468, 'EndOffset': 470}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 472, 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