Summary of medicine characteristics - Protopy
3. PHARMACEUTICAL FORM
t adequately responsive to or Treatment of moderate to led to respond adequately to
Ointment
A white to slightly yellowish ointment.
4.
4.1
Treatment of moderate to severe atopic dermatitis in adults wh are intolerant of conventional therapies such as topical corticos severe atopic dermatitis in children (2 years of age and above) conventional therapies such as topical corticosteroids.
4.2 Posology and method of administrationperience in the diagnosis and treatment of atopic
Protopy should be initiated by physicians dermatitis.
ontinuous.
Treatment should be intermittent a
Protopy ointment should be app as a thin layer to affected areas of the skin. Protopy ointment may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Protopy ointment sh ot be applied under occlusion (see section 4.4).
Each affected region of the skin should be treated with Protopy until clearance occurs and then treatment should be discontinued. 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. Protopy can be used for short term and intermittent long term treatment. At the first signs of recurrence (flares) of the disease symptoms, treatment should be re-initiated.
py is not recommended for use in children below age of 2 years until further data are available.
Use in children (2 years of age and above)
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).
Use in adults (16 years of age and above)
Protopy is available in two strengths, Protopy 0.03% and Protopy 0.1% ointment. Treatment should be started with Protopy 0.1% twice a day and treatment should be continued until clearance of the lesion. If symptoms recur, twice daily treatment with Protopy 0.1% should be restarted. An attempt should be made to reduce the frequency of application or to use the lower strength Protopy 0.03% ointment if the clinical condition allows.
Use in elderly (65 years of age and above)
Specific studies have not been conducted in elderly patients. However, the clinical experience available in this patient population has not shown the necessity for any dosage adjustment.
As clinical efficacy studies were performed with abrupt cessation of treatment, no information is available on whether tapering of the dosage would reduce recurrence rate.
4.3 Contraindications
Hypersensitivity to macrolides in general, to tacrolimus or to any of the excipients.
4.4 Special warnings and precautions for use
Protopy should not be used in patients with congenital or acquired immunodeficiencies on therapy that cause immunosuppression.
The effect of treatment with Protopy ointment on the developing immune system of children, especially the young, has not yet been established and this should be taken into account when prescribing to this age group (see section 4.1).
Exposure of the skin to sunlight should be minimised and the use o olet (UV) light from a solarium, therapy with UVB or UVA in combination with psoralen ) should be avoided during use of Protopy 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. Protopy ointment should not be applied to lesions that are considered to be potentially malignant or pre-malignant.
Emollients should not be applied to the same area within 2 hours of applying Protopy ointment. Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.
Protopy ointment has not been eva infected atopic dermatitis. Before treatment sites should be cleared. infections. Treatment with Prot
d for its efficacy and safety in the treatment of clinically ncing treatment with Protopy ointment, clinical infections at ients with atopic dermatitis are predisposed to superficial skin may be associated with an increased risk of herpes viral infections (herpes simplex dermatitis [eczema herpeticum], herpes simplex [cold sores], Kaposi’s varicelliform eruption). In the presence of these infections, the balance of risks and benefits associated with Protopy use should be evaluated.
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).
Protop prolon
s the active substance tacrolimus, a calcineurin inhibitor. In transplant patients, mic exposure to intense immunosuppression following systemic administration of
rin inhibitors has been associated with an increased risk of developing lymphomas and skin ignancies. In patients using tacrolimus ointment, cases of malignancies, including cutaneous and er types of lymphoma, and skin cancers have been reported (see section 4.8). Patients with atopic ermatitis treated with Protopy have not been found to have significant systemic tacrolimus levels.
Lymphadenopathy was uncommonly (0.8%) reported in clinical trials. The majority of these cases 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 Protopy 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 Protopy should be considered.
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 Protopy 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 failur (see section 5.2).
The use of Protopy ointment in patients with genetic epidermal barrier defects such as Netherton’s syndrome is not recommended due to the potential for permanently increased systemic absorption of tacrolimus. The safety of Protopy ointment has not been established in patients with generalised erythroderma.
Care should be exercised if applying Protopy to patients with extensive ski extended period of time, especially in children (see section 4.2).
ement over an
4.5 Interaction with other medicinal products and other fo
Formal topical drug interaction studies with tacrolimus oin
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 metab Systemic exposure from topical applicatio to be affected by concomitant use of su
possibility of interactions cannot b CYP3A4 inhibitors (e.g. erythromyci widespread and/or erythrodermi
olised via the hepatic Cytochrome P450 3A4 (CYP3A4).
of tacrolimus ointment is low (< 1.0 ng/ml) and is unlikely nces known to be inhibitors of CYP3A4. However, the ut and the concomitant systemic administration of known
itraconazole, ketoconazole and diltiazem) in patients with se should be done with caution.
A potential interaction b
investigated. Becaus prior to commencem between the last appl period should be ext
f th
een vaccination and application of Protopy ointment has not been e potential risk of vaccination failure, vaccination should be administered treatment, or during a treatment-free interval with a period of 14 days
ication of Protopy and the vaccination. In case of live attenuated vaccination, this nded to 28 days or the use of alternative vaccines should be considered.
4.6
re are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals e shown reproductive toxicity following systemic administration (see section 5.3). The potential for humans is unknown.
Protopy 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 is low, breast-feeding during treatment with Protopy ointment is not recommended.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Protopy ointment is administered topically and is unlikely to have an effect on the ability to drive or 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 application were also commonly observed. Alcohol intolerance (facial flushing or skin irritation afte 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 or Frequencies are defined as very common (> 1/10), common (> 1/100, < 1/10) an (> 1/1,000, < 1/100). Within each frequency grouping, undesirable effects are pr decreasing seriousness.
er of
General disorders and administration site conditions
Very common:
Common:
Application site burning, application site pruritus
Application site warmth, application site erythema, application site pain, application site irritation, application site paraesthesia, application site rash
Infections and infestations
Common:
Paraesthesias a
Folliculitis, pruritus Acne
atitis [eczema herpeticum], herpes eruption)
Herpes viral infections (herpes simple simplex [cold sores], Kaposi’s varicelli
Skin and subcutaneous tissue disorders
Common:
Uncommon:
Nervous system disorders
Common:
Metabolism and nutrition di
Common:
sthesias (hyperaesthesia, burning sensation)
Alcohol nce (facial flushing or skin irritation after consumption of an alcoholic beverage)
The following adverse reactions have been reported during post-marketing experience: Skin and subcutaneous tissue disorders: Rosacea
Post-m cancers
verdose
cases of malignancies, including cutaneous and other types of lymphoma, and skin een reported in patients using tacrolimus ointment (see section 4.4).
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 PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AX14
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 calciumdependent signal transduction pathways in T cells, thereby preventing the transcription and synthesi of IL-2, IL-3, IL-4, IL-5 and other cytokines such as GM-CSF, TNF-a and IFN-y.
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.
pontaneous educe skin
In animals, tacrolimus ointment suppressed inflammatory reactions in experime dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment di thickness and did not cause skin atrophy in animals.
ith tacrolimus and a reduction of ot affect collagen synthesis
In patients with atopic dermatitis, improvement of skin lesions durin ointment was associated with reduced Fc receptor expression on La their hyperstimulatory activity towards T cells. Tacrolimus ointmen in humans.
Results from clinical studies in patients
The efficacy and safety of Protopy was assessed in more than 13,500 patients treated with tacrolimus ointment in Phase I to Phase III clinical trials. Data from four 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). Th
se rates at month 6 were comparable to the 3-month results.
Table 1
at mon
| 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) | k | |
| 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 Decrease (Primary Endpoint)§ [ | 47.2% J | 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.
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 oi (0.03%) had blood concentrations < 1.0 ng/ml. When observed, blood concentrations exceedi
1.0 ng/ml were transient. Systemic exposure increases with increasing treatment areas. the extent and the rate of topical absorption of tacrolimus decrease as the skin heals. In children with an average of 50% body surface area treated, systemic exposure (i.e. AU
ver, both
from Protopy is approximately 30-fold less than that seen with oral immunosup kidney and liver transplant patients. The lowest tacrolimus blood concentration effects can be observed is not known.
adults and ) of tacrolimus doses in
t which systemic
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 h plasma proteins is considered not to be clinically relevant.
Following topical application of tacrolimus ointment, tacroli with minimal diffusion into the systemic circulation.
Metabolism
g of tacrolimus (> 98.8%) to
us is selectively delivered to the skin
Metabolism of tacrolimus by human skin extensively metabolised in the liver via C
t detectable. Systemically available tacrolimus is
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 cotreated with drugs th potent inhibitors of CYP3A4.
Following repeatel application of the ointment the average half-life of tacrolimus was estimated to be 75 for adults and 65 hours for children.
5.3 Prec
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 signi toxicity in maternal animals. Reduced sperm function was noted in male rats at high subcut doses of tacrolimus.
6. PHARMACEUTICAL PARTICULARS
6.2 Incompatibilities
Not applicable.
6.4 Special precautio
Do not store above
White soft paraffin Liquid paraffin Propylene carbonate White beeswax Hard paraffin
6.5 Nature
6.3 Shelf life
6.1 List of excipients
torage
ntents of container
3 years
Lamin screw
with an inner lining of low-density-polyethylene fitted with a white polypropylene ge sizes: 10 g, 30 g and 60 g. Not all pack sizes may be marketed.
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Astellas Pharma GmbH Neumarkter Str. 61 D-81673 München Germany
8. MARKETING AUTHORISATION NUMBERS
EU/1/02/202/001
EU/1/02/202/002
EU/1/02/202/005
the website of the European Medicines
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISA
Date of first authorisation: 28/02/2002
Date of renewal: 20/11/2006
10. DATE OF REVISION OF THE TEXT{DD/MM/YYYY}
Detailed information on this medicinal product is availab Agency (EMEA)