PROTOPIC 0.1% Ointment Ref.[7763] Active ingredients: Tacrolimus

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.

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.

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).

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.

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 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.

Infections and infestations

Common: 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

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

Nervous system disorders

Common: Paraesthesias and dysaesthesias (hyperaesthesia, burning sensation)

Skin and subcutaneous tissue disorders

Common: Pruritus

Uncommon: Acne*

Not known: Rosacea*, Lentigo*

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

Not known: Application site oedema*

Investigations

Not known: 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.

Not applicable.