Protopic 0.1% Ointment

addition of warning and precautions for patients with pyoderma gangrenosum 

addition of warning and precautions for patients with pyoderma gangrenosum 

Document format updated - SPC pdf to html

Local representative contact details updated

4.2 - added excipients with known effect

Excipient with known effect

Butylhydroxytoluene (E321) 15 micrograms/g ointment.

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4.4 - Editorial changes (Older people --> Elderly) + addition of excipient warning:

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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.

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4.6 - relocation of fertility from beginning of section to end of sections

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5.2 - editorial change to the heading metabolism --> biotransformation

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6 addition of excipients:

Butylhydroxytoluene (E321)

All-rac-α-tocopherol

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of Protopic 0.03% ointment contains 0.3 mg of tacrolimus as tacrolimus monohydrate (0.03%).

For thea full list of excipients, see section 6.1.

4.2     Posology and method of administration

Elderly Older peoplepatients

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

Older peopleElderly patients

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

4.3     Contraindications

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

4.6     Fertility, Pregnancy and lactation

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.

4.7     Effects on ability to drive and use machines

Protopic ointment has no or negligibleis administered topically and is unlikely to have an effect influenceeffect on the ability to drive or use machines.

4.8     Undesirable effects

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 online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Astellas Pharma Europe B.V.

Sylviusweg 62

2333 BE Leiden

Netherlands

4.4     Special warnings and precautions for use

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.

4.8     Undesirable effects

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).

4.4       Special warnings and precautions for use

Protopic should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that cause immunosuppression.

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).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.

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 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).

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.

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.

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 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.

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).

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.

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).

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).

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).

The development of any new change different from previous eczema within a treated area should be reviewed by the physician.

10.       DATE OF REVISION OF THE TEXT

July 2012

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 can be used for short-term and intermittent long-term treatment. Treatment should not be continuous.

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.

4.4     Special warnings and precautions for use

The use of  Protopic tacrolimus ointment is not recommended in patients with a skin genetic epidermal 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.

is not recommended due to the potential for permanently increased systemic absorption of tacrolimus. The safety of Protopic ointment has not been established in patients with generalised erythroderma

4.8     Undesirable effects

General disorders and administration site conditions

Very common:     Application site burning, application site pruritus

Common:             Application site warmth, application site erythema, application site pain, application site irritation, application site paraesthesia, application site rash

Infections and infestations

4.2  Posology and method of administration

Protopic can be used for short-term and intermittent long-term treatment.  Treatment should not be continuous.

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.

4.4 Special warnings and precautions for use

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 skin conditions. Post-Marketing cases of increased tacrolimus blood level have been reported in these conditions.

4.8 Undesirable effect

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AH01

10. DATE OF REVISION OF THE TEXT

Feb 2011

Section  4.1     Therapeutic indications update

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.

Was updated to read:

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 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).

Section  4.2     Posology and method of administration

The sentence: Treatment should be intermittent and not continuous was removed and replaced by:

Protopic can be used for short-term and intermittent long-term treatment. Treatment should not be continuous.

Protopic ointment should be applied as a thin layer to affected areas of the skin., was changed to read: Protopic ointment should be applied as a thin layer to affected or commonly affected areas of the skin.

The following paragraphs were omitted:

Each affected region of the skin should be treated with Protopic 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. Protopic 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.

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.

The following paragraph was inserted:

Treatment

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.

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.

Maintenance

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.

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 23 days without Protopic treatment.

Adult patients (16 years of age and above) should use Protopic 0.1% ointment, children (2 years of age and above) should use the lower strength Protopic 0.03% ointment.

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

After 12 months, 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. In children, this review should include suspension of treatment to assess the need to continue this regimen and to evaluate the course of the disease.

Section 4.4      Special warnings and precautions for use

The following sentence was inserted: The development of any new change different from previous eczema within a treated area should be reviewed by the physician.

Section 4.8      Undesirable effects

The following paragraf was added:

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).

Section 5.1      Pharmacodynamic properties

The following paragraph was inserted:

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 (Investigators 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)

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

Section 7: MARKETING AUTHORISATION HOLDER

Updated from:

Astellas Pharma GmbH

Neumarkter Str. 61

D-81673 Mnchen

Germany

To

Astellas Pharma Europe B.V.

Elisabethhof 19

2353 EW Leiderdorp

Netherlands

Section 10.      DATE OF REVISION OF THE TEXT

Updated from 03/05/2007 to April 2009

Changes Document

Protopic 0.03% and 0.1% SPC

May 2007 v Nov 2006

5.2     Pharmacokinetic properties

Absorption

Correction of the adult high dose from 0.3% to 0.1%, and insertion of data from infants from age of 5 months, as follows:

5.3 Clinical Data

Reproduction toxicity

Correction: Reduced sperm function was noted in male rats at high subcutaneous doses as opposed to high oral doses, as had stated in the previous version of the SPC.

10. Date of Revision of Text

Updated from 20/11/2006 to 03/05/2007

EMEA website address updated from http://www.emea.eu.int/ to http://www.emea.europa.eu

Changes Document – Protopic SPC

June 2006 v Nov 2006

Changes apply to both strengths (0.03% 0.1%)

No changes to the content  were introduced. However, the whole product information was adjusted to the QRD 7.1 template which required mainly changes of template sentences and rearrangements of whole paragraphs.

Section 2:

Insertion of new text: “For a full list of excipients, see section 6.1”.

Section 4.4:

Re-wording of heading: “Special warnings and special precautions for use”

Section 4.6

First paragraph: wording re-arranged but content unchanged.

Insertion of new text: “Protopic ointment should not be used during pregnancy unless clearly necessary”.

Section 4.8:

Insertion of new text: “Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness”.

Section 6.6

Re-wording of heading: “Instructions for use and handling and Special precautions for disposal”

Insertion of new text: “Any unused product or waste material should be disposed of in accordance with local requirements”.

Section 9

Date of first authorisation changed to: 28/02/2002

Date of renewal: 20/11/2006

Section 10

Date of revision of the text: 20/11/2006

Insertion of new text: “Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.eu.int/”