PROTOPIC 0.1% ointment medication leaflet

Protopic 0.1% ointment

1 g of Protopic 0.1% ointment contains 1.0 mg of tacrolimus as tacrolimus monohydrate (0.1%).

Butylhydroxytoluene (E321) 15 micrograms/g ointment.

For the full list of excipients, see section 6.1.

Ointment

A white to slightly yellowish ointment.

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 orare intolerant of conventional therapies such as topical corticosteroids.

Treatment of moderate to severe atopic dermatitis for the prevention of flares and the prolongation offlare-free intervals in patients experiencing a high frequency of disease exacerbations (i.e. occurring 4or more times per year) who have had an initial response to a maximum of 6 weeks treatment of twicedaily tacrolimus ointment (lesions cleared, almost cleared or mildly affected).

Protopic treatment should be initiated by physicians with experience in the diagnosis and treatment ofatopic dermatitis.

Protopic is available in two strengths, Protopic 0.03 % and Protopic 0.1 % ointment.

Flare treatment

Protopic can be used for short-term and intermittent long-term treatment. Treatment should not becontinuous on a long-term basis.

Protopic treatment should begin at the first appearance of signs and symptoms. Each affected region ofthe 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 ofrecurrence (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 untilclearance of the lesion. If symptoms recur, twice daily treatment with Protopic 0.1% should berestarted. An attempt should be made to reduce the frequency of application or to use the lowerstrength Protopic 0.03% ointment if the clinical condition allows.

Generally, improvement is seen within one week of starting treatment. If no signs of improvement areseen after two weeks of treatment, further treatment options should be considered.

Specific studies have not been conducted in older people. However, the clinical experience availablein this patient population has not shown the necessity for any dosage adjustment.

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.

Patients who are responding to up to 6 weeks treatment using tacrolimus ointment twice daily (lesionscleared, 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 ointmentshould be applied once a day twice weekly (e.g. Monday and Thursday) to areas commonly affectedby atopic dermatitis to prevent progression to flares. Between applications there should be 2-3 dayswithout Protopic treatment.

After 12 months treatment, a review of the patient`s condition should be conducted by the physicianand a decision taken whether to continue maintenance treatment in the absence of safety data formaintenance treatment beyond 12 months.

If signs of a flare reoccur, twice daily treatment should be re-initiated (see flare treatment sectionabove).

Specific studies have not been conducted in older people (see flare treatment section above).

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.

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, excepton mucous membranes. Protopic ointment should not be applied under occlusion because this methodof administration has not been studied in patients (see section 4.4).

Hypersensitivity to the active substance, macrolides in general, or to any of the excipients listed insection 6.1.

Exposure of the skin to sunlight should be minimised and the use of ultraviolet (UV) light from asolarium, therapy with UVB or UVA in combination with psoralens (PUVA) should be avoidedduring use of Protopic ointment (see section 5.3). Physicians should advise patients on appropriate sunprotection methods, such as minimisation of the time in the sun, use of a sunscreen product andcovering of the skin with appropriate clothing. Protopic ointment should not be applied to lesions thatare considered to be potentially malignant or pre-malignant. The development of any new changedifferent 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, pyoderma gangrenosum orcutaneous Graft Versus Host Disease. These skin conditions may increase systemic absorption oftacrolimus. Post-marketing cases of increased tacrolimus blood level have been reported in theseconditions. Protopic should not be used in patients with congenital or acquired immunodeficiencies orin patients on therapy that cause immunosuppression.

Care should be exercised if applying Protopic to patients with extensive skin involvement over anextended period of time, especially in children (see section 4.2). Patients, particularly paediatricpatients should be continuously evaluated during treatment with Protopic with respect to the responseto treatment and the continuing need for treatment. After 12 months this evaluation should includesuspension of Protopic treatment in paediatric patients (see section 4.2).

Protopic contains the active substance tacrolimus, a calcineurin inhibitor. In transplant patients,prolonged systemic exposure to intense immunosuppression following systemic administration ofcalcineurin inhibitors has been associated with an increased risk of developing lymphomas and skinmalignancies. Patients with atopic dermatitis treated with Protopic have not been found to havesignificant systemic tacrolimus levels and the role of local immunosuppression is unknown.

Based on the results of long-term studies and experience, a link between Protopic ointment treatmentand development of malignancies has not been confirmed, but definitive conclusions cannot be drawn.

It is recommended to use tacrolimus ointment at the lowest strength and the lowest frequency for theshortest duration necessary as determined by the physician’s evaluation of the clinical condition (seesection 4.2).

Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these caseswere related to infections (skin, respiratory tract, tooth) and resolved with appropriate antibiotictherapy. Lymphadenopathy present at initiation of therapy should be investigated and kept underreview. In case of persistent lymphadenopathy, the aetiology of the lymphadenopathy should beinvestigated. In the absence of a clear aetiology for the lymphadenopathy or in the presence of acuteinfectious mononucleosis, discontinuation of Protopic should be considered. Patients who developlymphadenopathy during treatment should be monitored to ensure that the lymphadenopathy resolves.

Patients with atopic dermatitis are predisposed to superficial skin infections. Protopic ointment has notbeen 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 becleared. Treatment with Protopic is associated with an increased risk of folliculitis and herpes viralinfections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi’svaricelliform eruption) (see section 4.8). In the presence of these infections, the balance of risks andbenefits 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 withconcomitant use of systemic steroids or immunosuppressive agents.

Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied tothese 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 arenot recommended.

As with any topical medicinal product, patients should wash their hands after application if the handsare not intended for treatment.

Tacrolimus is extensively metabolised in the liver and although blood concentrations are lowfollowing 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 skinreactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

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 percutaneousinteractions 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 unlikelyto be affected by concomitant use of substances known to be inhibitors of CYP3A4. However, thepossibility of interactions cannot be ruled out and the concomitant systemic administration of known

CYP3A4 inhibitors (e.g. erythromycin, itraconazole, ketoconazole and diltiazem) in patients withwidespread and/or erythrodermic disease should be done with caution.

An interaction study with protein-conjugated vaccine against Neisseria menigitidis serogroup C hasbeen investigated in children aged 2-11 years. No effect on immediate response to vaccination, thegeneration of immune memory, or humoral and cell-mediated immunity has been observed (seesection 5.1).

There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animalshave shown reproductive toxicity following systemic administration (see section 5.3). The potentialrisk for humans is unknown.

Protopic ointment should not be used during pregnancy unless clearly necessary.

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 islow, breast-feeding during treatment with Protopic ointment is not recommended.

There are no fertility data available.

Protopic ointment has no or negligible influence on the ability to drive and use machines.

In clinical studies approximately 50% of patients experienced some type of skin irritation adversereaction at the site of application. Burning sensation and pruritus were very common, usually mild tomoderate in severity and tended to resolve within one week of starting treatment. Erythema was acommon skin irritation adverse reaction. Sensation of warmth, pain, paraesthesia and rash at the site ofapplication were also commonly observed. Alcohol intolerance (facial flushing or skin irritation afterconsumption 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 ofdecreasing seriousness.

System Organ Very Common Common Uncommon Not known

Class ≥1/10 ≥1/100, ≥1/1000, (cannot be<1/10 <1/100 estimatedfrom theavailabledata)

Infections and Local skin infection Ophthalmicinfestations regardless of specific Herpesaetiology including but not Infection*limited to:

Eczema herpeticum,

Folliculitis,

Herpes simplex,

Herpes virus infection,

Kaposi’s varicelliformeruption*

Metabolism and Alcohol intolerance (facialnutrition flushing or skin irritationdisorders after consumption of analcoholic beverage)

Nervous system Paraesthesias anddisorders dysaesthesias(hyperaesthesia, burningsensation)

Skin and Pruritus Acne* Rosacea*subcutaneous Lentigo*tissue disorders

General disorders Application site Application site warmth, Applicationand burning, Application site erythema, site oedema*administration Application site Application site pain,site conditions pruritus Application site irritation,

Application siteparaesthesia,

Application site rash

Investigations Drug levelincreased*(see section4.4)

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

In a study of maintenance treatment (twice weekly treatment) in adults and children with moderate andsevere atopic dermatitis the following adverse events were noted to occur more frequently than in thecontrol group: application site impetigo (7.7% in children) and application site infections (6.4% inchildren and 6.3% in adults).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdosage following topical administration is unlikely.

If ingested, general supportive measures may be appropriate. These may include monitoring of vitalsigns and observation of clinical status. Due to the nature of the ointment vehicle, induction ofvomiting or gastric lavage is not recommended.

Pharmacotherapeutic group: Agents for dermatitis, excluding corticosteroids, ATC code: D11AH01

Mechanism of action and pharmacodynamic effects

The mechanism of action of tacrolimus in atopic dermatitis is not fully understood. While thefollowing have been observed, the clinical significance of these observations in atopic dermatitis is notknown.

Via its binding to a specific cytoplasmic immunophilin (FKBP12), tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesisof 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 stimulatoryactivity towards T cells. Tacrolimus has also been shown to inhibit the release of inflammatorymediators from skin mast cells, basophils and eosinophils.

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

In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimusointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction oftheir hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesisin humans.

The efficacy and safety of Protopic was assessed in more than 18,500 patients treated with tacrolimusointment 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 administeredtwice-a-day to adults with moderate to severe atopic dermatitis and compared to a topicalcorticosteroid 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 3defined 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% tacrolimusgroup (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 Tacrolimus 0.1%regimen§ (N=487)(N=485)

Response rate of ≥ 60% 50.8% 71.6%improvement in mEASI (Primary

Endpoint)§§

Improvement ≥ 90% in Physician’s 28.5% 47.7%

Global Evaluation§ 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. Skinburning, herpes simplex, alcohol intolerance (facial flushing or skin sensitivity after alcohol intake),skin tingling, hyperaesthesia, acne and fungal dermatitis occurred more often in the tacrolimustreatment group. There were no clinically relevant changes in the laboratory values or vital signs ineither treatment group throughout the study.

In the second trial, children aged from 2 to 15 years with moderate to severe atopic dermatitis receivedtwice 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 themEASI 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 significantlymore effective (p<0.001 for both) than 1% hydrocortisone acetate ointment (Table 2).

Table 2: Efficacy at week 3

Hydrocortisone Tacrolimus 0.03% Tacrolimus 0.1%acetate 1% (N=189) (N=186)(N=185)

Median mEASI as Percentage of 64.0% 44.8% 39.8%

Baseline mean AUC (Primary

Endpoint)§

Improvement  90% in Physician’s 15.7% 38.5% 48.4%

Global Evaluation§ lower values = greater improvement

The incidence of local skin burning was higher in the tacrolimus treatment groups than in thehydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in thehydrocortisone group. There were no clinically relevant changes in the laboratory values or vital signsin either treatment group throughout the clinical trial.

The purpose of the third multicentre, double-blind, randomised study was the assessment of efficacyand safety of 0.03% tacrolimus ointment applied once or twice a day relative to twice dailyadministration of 1% hydrocortisone acetate ointment in children with moderate to severe atopicdermatitis. Treatment duration was for up to three weeks.

Table 3: Efficacy at week 3

Hydrocortisone Tacrolimus 0.03% Tacrolimus 0.03%acetate 1% Once daily (N=207) Twice daily (N=210)

Twice daily (N=207)

Median mEASI Percentage 47.2% 70.0% 78.7%

Decrease (Primary Endpoint)§

Improvement 90% in 13.6% 27.8% 36.7%

Physician’s Global Evaluation§ higher values = greater improvement

The primary endpoint was defined as the percentage decrease in mEASI from the baseline to end oftreatment. A statistically significant better improvement was shown for once daily and twice daily0.03% tacrolimus ointment compared to twice daily hydrocortisone acetate ointment (p<0.001 forboth). Twice daily treatment with 0.03% tacrolimus ointment was more effective than once dailyadministration (Table 3). The incidence of local skin burning was higher in the tacrolimus treatmentgroups than in the hydrocortisone group. There were no clinically relevant changes in the laboratoryvalues or vital signs in either treatment group throughout the study.

In the fourth trial, approximately 800 patients (aged ≥2 years) received 0.1% tacrolimus ointmentintermittently or continuously in an open-label, long-term safety study for up to four years, with 300patients receiving treatment for at least three years and 79 patients receiving treatment for a minimumof 42 months. Based on changes from baseline in EASI score and body surface area affected, patientsregardless 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 overallincidence of adverse events tended to decrease as the study progressed for all patients independent ofage. 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 previouslyunreported 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 atopicdermatitis 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, patientswith active disease entered an open-label period (OLP) during which they treated affected lesions withtacrolimus 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. Patientswere randomised to receive either tacrolimus ointment (0.1% adults; 0.03% children) or vehicle, oncea day twice weekly on Mondays and Thursdays. If a disease exacerbation occurred, patients weretreated with open-label tacrolimus ointment twice daily for a maximum of 6 weeks until the IGA scorereturned to ≤2.

The primary endpoint in both studies was the number of disease exacerbations requiring a “substantialtherapeutic 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 daystreatment. Both studies showed significant benefit with twice weekly treatment with tacrolimusointment with regard to the primary and key secondary endpoints over a period of 12 months in apooled population of patients with mild to severe atopic dermatitis. In a subanalysis of a pooledpopulation of patients with moderate to severe atopic dermatitis these differences remainedstatistically significant (Table 4). No adverse events not reported previously were observed in thesestudies.

Table 4: Efficacy (moderate to severe subpopulation)

Adults, ≥16 years Children, 2-15 years

Tacrolimus 0.1% Vehicle Tacrolimus Vehicle

Twice weekly Twice weekly 0.03% Twice weekly(N=80) (N=73) Twice weekly (N=75)(N=78)

Median number of DEsrequiring substantial 1.0 (48.8%) 5.3 (17.8%) 1.0 (46.2%) 2.9 (21.3%)intervention adjusted fortime at risk (% of patientswithout DE requiringsubstantial intervention)

Median time to first DE 142 days 15 days 217 days 36 daysrequiring substantialintervention

Median number of DEsadjusted for time at risk 1.0 (42.5%) 6.8 (12.3%) 1.5 (41.0%) 3.5 (14.7%)(% of patients without any

DE periods)

Median time to first DE 123 days 14 days 146 days 17 days

Mean (SD) percentage of 16.1 (23.6) 39.0 (27.8) 16.9 (22.1) 29.9 (26.8)days of DE exacerbationtreatment

DE: disease exacerbation

P<0.001 in favour of tacrolimus ointment 0.1% (adults) and 0.03% (children) for the primary and keysecondary endpoints

A seven-month, double blind, randomised parallel group study of paediatric patients (2-11 years) withmoderate 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 comparatorarm 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 andsubsequently 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 ofpatients with a serum bactericidal antibody (SBA) titre ≥ 8 at the week 5 visit. Analysis of theresponse 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 weresimilar.

The primary response to vaccination was not affected.

Clinical data have shown that tacrolimus concentrations in systemic circulation after topicaladministration are low and, when measurable, transient.

Data from healthy human subjects indicate that there is little or no systemic exposure to tacrolimusfollowing single or repeated topical application of tacrolimus ointment.

Target trough concentrations for systemic immunosuppression for oral tacrolimus are 5-20 ng/mL intransplant patients. Most atopic dermatitis patients (adults and children) treated with single or repeatedapplication of tacrolimus ointment (0.03-0.1%), and infants from age of 5 months treated withtacrolimus ointment (0.03%) had blood concentrations < 1.0 ng/mL. When observed, bloodconcentrations exceeding 1.0 ng/mL were transient. Systemic exposure increases with increasingtreatment areas. However, both the extent and the rate of topical absorption of tacrolimus decrease asthe skin heals. In both adults and children with an average of 50% body surface area treated, systemicexposure (i.e. AUC) of tacrolimus from Protopic ointment is approximately 30-fold less than that seenwith oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimusblood 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) treatedfor prolonged periods (up to one year) with tacrolimus ointment.

As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) toplasma proteins is considered not to be clinically relevant.

Following topical application of tacrolimus ointment, tacrolimus is selectively delivered to the skinwith minimal diffusion into the systemic circulation.

Metabolism of tacrolimus by human skin was not detectable. Systemically available tacrolimus isextensively metabolised in the liver via CYP3A4.

When administered intravenously, tacrolimus has been shown to have a low clearance rate. Theaverage total body clearance is approximately 2.25 l/h. The hepatic clearance of systemically availabletacrolimus 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 wasestimated to be 75 hours for adults and 65 hours for children.

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).

Repeated dose toxicity and local tolerance

Repeated topical administration of tacrolimus ointment or the ointment vehicle to rats, rabbits andmicropigs 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 ofkidneys, pancreas, eyes and nervous system. The changes were caused by high systemic exposure ofrodents resulting from high transdermal absorption of tacrolimus. Slightly lower body weight gain infemales 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, reversiblecardiotoxic effects being observed.

In vitro and in vivo tests did not indicate a genotoxic potential of tacrolimus.

Systemic carcinogenicity studies in mice (18 months) and rats (24 months) revealed no carcinogenicpotential of tacrolimus.

In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumourswere observed. In the same study an increased incidence of lymphoma was detected in associationwith high systemic exposure.

In a photocarcinogenicity study, albino hairless mice were chronically treated with tacrolimus ointmentand UV radiation. Animals treated with tacrolimus ointment showed a statistically significant reductionin time to skin tumour (squamous cell carcinoma) development and an increase in the number of tumours.

This effect occurred at the higher concentrations of 0.3% and 1%. The relevance to humans is currentlyunknown. It is unclear whether the effect of tacrolimus is due to systemic immunosuppression or a localeffect. The risk for humans cannot be completely ruled out as the potential for local immunosuppressionwith 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 significanttoxicity in maternal animals. Reduced sperm function was noted in male rats at high subcutaneousdoses of tacrolimus.

White soft paraffin

Liquid paraffin

Propylene carbonate

White beeswax

Hard paraffin

Butylhydroxytoluene (E321)

All-rac-α-tocopherol

Not applicable.

3 years

Do not store above 25°C.

Laminate tube with an inner lining of low-density-polyethylene fitted with a white polypropylenescrew cap.

Package sizes: 10 g, 30 g and 60 g.

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

LEO Pharma A/S

Industriparken 552750 Ballerup

Denmark

EU/1/02/201/003

EU/1/02/201/004

EU/1/02/201/006

Date of first authorisation: 28 February 2002

Date of latest renewal: 20 November 2006

Detailed information on this medicinal product is available on the website of the European Medicines

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