Active ingredients: Tacrolimus (Tacrolimus monohydrate)
Protopic 0.03% ointment
Protopic package inserts are available for pack sizes:- Protopic 0.03% ointment
- Protopic 0.1% ointment
Indications Why is Protopic used? What is it for?
The active substance in Protopic, tacrolimus monohydrate, is an immunomodulating agent.
Protopic 0.03% ointment is indicated for the treatment of moderate to severe atopic dermatitis (eczema) in adults who do not respond adequately or who are intolerant to conventional therapies such as topical corticosteroids and in children (2 years and older) who they did not respond adequately to conventional therapies such as topical corticosteroids.
If moderate to severe atopic dermatitis has disappeared or almost disappeared after treatment of exacerbations for up to 6 weeks, and if frequent exacerbations occur (4 or more per year), they can be prevented or prolonged. they do not occur with the use of Protopic 0.03% ointment twice a week.
In atopic dermatitis there is an overreaction of the skin's immune system which causes skin inflammation (itching, redness, dryness). Protopic modifies the abnormal immune response and relieves skin inflammation and itching.
Contraindications When Protopic should not be used
Do not use Protopic
- If you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Protopic or to macrolide antibiotics (i.e. azithromycin, clarithromycin, erythromycin).
Precautions for use What you need to know before taking Protopic
Tell your doctor
- if you have liver failure.
- if you have any skin malignancies (neoplasia) or if you have a weakened (immunocompromised) immune system, whatever the cause.
- if you have a congenital skin disease such as Netherton's syndrome, lamellar ichthyosis (widespread peeling of the skin caused by thickening of the outer skin layer) or if you suffer from generalized erythroderma (redness from inflammation and peeling of the whole skin).
- if you experience cutaneous Graft Versus Host Disease (a skin immune reaction which is a common complication in bone marrow transplant patients).
- if you have swollen lymph nodes at the start of treatment. If your lymph nodes swell 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 in the appearance of your skin, please tell your doctor.
- The safety of using Protopic over a long period of time is not known. A very small number of people who have used Protopic ointment have had malignancies (eg, skin or lymphomas). However, a link has not been shown. with Protopic ointment treatment.
- Avoid exposing your skin for long periods to sunlight or artificial light such as a tanning bed. If you spend time outdoors after applying Protopic, use a sunscreen and wear comfortable clothing that protects your skin from the sun. Also, consult your doctor for other appropriate methods of sun protection. If you have been prescribed heliotherapy, please tell your doctor that you are using Protopic and that it is not recommended to use Protopic and sun therapy at the same time .
- If your doctor prescribes Protopic for you twice a week to avoid a new onset of your atopic dermatitis, your condition should be re-evaluated by your doctor at least every 12 months even if the disease is under control. In children, maintenance treatment should be stopped after 12 months to check whether there is still a need for continued treatment.
Children
- Protopic ointment is not approved for use in children under 2 years of age. It should therefore not be used in this age group. Please consult your doctor.
- The effect of Protopic treatment on the development of the immune system of children, especially young people, has not been established.
Interactions Which drugs or foods may change the effect of Protopic
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
You can use moisturizing creams and lotions during Protopic treatment, however they can only be applied to the same treated area two hours before or two hours after Protopic application.
The effect of concurrent use of Protopic with other preparations to be applied to the skin or with the intake of oral corticosteroids (eg cortisone) or medicines that affect the immune system has not been studied.
Protopic with alcoholic beverages
While using Protopic, drinking alcoholic beverages may cause flushing of the face or skin and sensations of heat
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use Protopic if you are pregnant or breastfeeding.
Ask your doctor or pharmacist for advice before taking any medicine
Dose, Method and Time of Administration How to use Protopic: Posology
Always use Protopic exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
- Apply a thin layer of Protopic to the affected areas of the skin.
- Protopic can be applied to most of the body surface, including the face, neck and areas subject to flexion of the elbows and knees.
- Avoid using the ointment in your nose, mouth or eyes. If the ointment is accidentally applied to these areas, the area will need to be cleaned up completely and / or rinsed with water.
- Do not cover the affected area of skin with bandages or dressings.
- Wash your hands after applying Protopic, unless your hands are also within the area to be treated.
- Before applying Protopic after a bath or shower, make sure your skin is completely dry.
Use in children (2 years of age and older)
Apply Protopic 0.03% ointment twice a day for three weeks, once in the morning and once in the evening. Thereafter, the ointment should be used once a day on each affected skin area until the eczema has healed.
Adults (aged 16 and over)
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 dosage will be best for you.
Generally, treatment starts with Protopic 0.1% twice a day, once in the morning and once in the evening, until the eczema has disappeared. Based on the response of the eczema, the doctor will decide whether the frequency of applications will be reduced or if the lower strength (Protopic 0.03%) can be used.
Treat affected areas of skin until the eczema heals. Generally you see improvement within one week. Consult your doctor about other types of treatment if you do not see any visible improvement after two weeks.
Your doctor may prescribe you to use Protopic ointment twice a week after your atopic dermatitis has disappeared or almost disappeared (Protopic 0.03% for children and Protopic 0.1% for adults). Protopic ointment should be applied once a day, twice a week (for example, Monday and Thursday) on the areas of your body normally affected by atopic dermatitis 2-3 days should elapse between applications without Protopic treatment.
If symptoms reappear, return to using Protopic twice a day as described above and make an appointment with your doctor to check your therapy.
Overdose What to do if you have taken too much Protopic
If you accidentally swallow the 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, apply it as soon as you remember, then continue as prescribed. If you have any further questions on the use of Protopic, ask your doctor or pharmacist.
Side Effects What are the side effects of Protopic
Like all medicines, Protopic can cause side effects, although not everybody gets them.
Very common (may affect more than 1 in 10 people):
- Sensation of burning and itching
These symptoms are usually mild to moderate and generally disappear within one week of starting treatment with Protopic.
Common (may affect up to 1 in 10 people):
- Redness
- Feeling of heat
- Ache
- Increased skin sensitivity (especially in heat and cold)
- Skin tingling
- Rash Local skin infection regardless of specific causes, including but not limited to: inflamed or infected hair follicles, cold sores, generalized herpes simplex infections)
- Facial flushing or skin irritation after consuming alcoholic beverages are also common reactions
Uncommon (may affect less than 1 in 100 people):
- Acne
Application site infections have been reported in children and adults following twice weekly treatment. Impetigo, a superficial bacterial skin infection that usually causes blisters or sores on the skin, has been reported in children.
Rosacea (facial flushing), pseudo-rosacea dermatitis and application site edema have been reported during the post-marketing period.
Since its availability on the market, a very small number of people who have used Protopic ointment have had malignant tumors (e.g. lymphomas, including skin lymphomas or other skin cancers). However, a correlation with Protopic ointment treatment has not been demonstrated or excluded based on the data available to date.
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.
Expiry and Retention
Keep Protopic out of the reach and sight of children.
Do not use Protopic after the expiry date which is stated on the tube and carton after EXP. The expiry date refers to the last day of the month.
Do not store above 25ºC.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Protopic contains
- The active ingredient is tacrolimus monohydrate. One gram of Protopic 0.03% ointment contains 0.3 mg of tacrolimus (as tacrolimus monohydrate).
- The other ingredients are white petroleum jelly, liquid paraffin, propylene carbonate, white beeswax and solid paraffin.
What Protopic looks like and contents of the pack
Protopic is a white, slightly yellowish ointment. It is available in tubes of 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).
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
PROTOPIC 0.03% OIL
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 g of Protopic 0.03% ointment contains 0.3 mg of tacrolimus as tacrolimus monohydrate (0.03%).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Ointment.
White to slightly yellow ointment.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Protopic 0.03% ointment is indicated in adults, adolescents and children from 2 years of age.
Treatment of exacerbations
Adults and adolescents (aged 16 years and over)
Treatment of moderate to severe atopic dermatitis in adults who do not respond adequately or who are intolerant to conventional therapies such as topical corticosteroids.
Pediatric population (aged 2 years and older)
Treatment of moderate to severe atopic dermatitis in children who have failed to respond to conventional therapies such as topical corticosteroids.
Maintenance treatment
Treatment of moderate to severe atopic dermatitis for the prevention of exacerbations and for the prolongation of exacerbation-free intervals in patients with very frequent exacerbations (4 or more times per year) who have experienced an initial response to treatment lasting a maximum of 6 weeks with tacrolimus ointment twice daily (lesions disappeared, almost disappeared or present in a mild form).
04.2 Posology and method of administration
Protopic treatment should be initiated by physicians experienced in the diagnosis and treatment of atopic dermatitis.
Protopic is available in two strengths, Protopic 0.03% and Protopic 0.1% ointment.
Dosage
Treatment of exacerbations
Protopic can be used for short-term treatment and for intermittent long-term treatment. Long-term treatment does not have to be continuous.
Protopic treatment should begin at the first appearance of signs and symptoms. Each affected area of skin should be treated with Protopic until the lesions have disappeared, almost disappeared or are present only slightly. Thereafter, patients are considered eligible for maintenance treatment (see below). At the first signs of recovery (exacerbation) of the symptoms of the disease, treatment should be restored.
Use in adults and adolescents (aged 16 years and over)
Treatment should start with Protopic 0.1% twice daily and should continue until the lesion is gone. If symptoms recur, treatment with Protopic 0.1% should be restarted twice daily. If clinical conditions permit, an attempt should be made to reduce the frequency of applications or to use the lower strength, Protopic 0.03% ointment.
Improvement is usually seen within one week of starting treatment. If no signs of improvement are seen after two weeks of treatment, other treatment options should be considered.
Elderly population
No specific studies have been conducted in the elderly population. However, the clinical experience available for this group of patients did not indicate a need for dose modification.
Pediatric population
Children (2 years of age and older) should use the lowest concentration: Protopic 0.03% ointment.
Treatment should start twice a day for up to three weeks.
Thereafter, the frequency of applications should be reduced to once daily until the lesion disappears (see section 4.4).
Protopic ointment should not be used in children below 2 years of age until further data become available.
Maintenance treatment
Patients who respond for up to 6 weeks of treatment with tacrolimus ointment twice daily (lesions disappeared, almost disappeared or present in a mild form) are eligible for maintenance treatment.
Adults and adolescents (aged 16 years and over)
Adult patients should use Protopic 0.1% ointment.
Protopic ointment should be applied once a day twice a week (for example, Monday and Thursday) to the areas usually affected by atopic dermatitis to prevent flare-ups.
Between applications there should be 2-3 days of discontinuing Protopic treatment.
After 12 months of treatment, the physician should re-evaluate the patients' condition to decide whether to continue maintenance treatment in the absence of data on the safety of maintenance treatment beyond 12 months.
If signs of exacerbation reoccur, treatment should be resumed twice daily (see previous section on treatment of exacerbations).
Elderly population
No specific studies have been conducted in the elderly population (see previous section on the treatment of exacerbations).
Pediatric population
Children (2 years of age and older) should use the lowest concentration: Protopic 0.03% ointment.
Protopic ointment should be applied once a day twice a week (for example, Monday and Thursday) to the areas usually affected by atopic dermatitis to prevent progression to flare-up. Between applications there should be 2-3 days of discontinuing Protopic treatment.
Assessment of the child's condition after 12 months of treatment should include discontinuation of treatment to ascertain the need to continue this regimen and to assess the course of the disease.
Protopic ointment should not be used in children below 2 years of age until further data become available.
Method of administration
A thin layer of Protopic ointment should be applied to affected or usually affected areas of the skin.
Protopic ointment can be applied to all parts of the body, including the face, neck and areas subject to flexion, with the exception of the mucous membranes. Protopic ointment should not be applied with occlusive dressings as no studies have been conducted on this method of administration (see section 4.4).
04.3 Contraindications
Hypersensitivity to the active substance, to macrolides in general or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
During the use of Protopic ointment excessive exposure of the skin to sunlight should be reduced and the use of ultraviolet (UV) light emitted by solarium and UVB or UVA therapy in combination with psoralens (PUVA) should be avoided. (See section 5.3) The physician should advise the patient on an appropriate method of sun protection, such as minimizing sun exposure time, using a product with a sunscreen, and covering the skin with appropriate clothing. Protopic ointment should not be applied to lesions that are considered potentially malignant or pre-malignant.
The development within the treated area of any changes other than existing eczema should be reviewed by the physician.
The use of tacrolimus ointment is not recommended in patients with skin barrier defects such as Netherton's syndrome, lamellar ichthyosis, generalized erythroderma or graft versus host disease. These skin conditions may increase the systemic absorption of tacrolimus. Oral administration of tacrolimus for the treatment of these skin conditions is also not recommended. There have been reports of increased blood levels of tacrolimus in the presence of the above conditions in the post-marketing setting. .
Caution should be exercised if Protopic is applied to patients with extensive skin involvement over a long period of time, particularly in children (see section 4.2). Patients, particularly pediatric patients, should be continually re-evaluated during treatment with Protopic to assess the response to treatment and whether it is necessary to continue treatment.
In pediatric patients, this reassessment after 12 months should include discontinuation of Protopic treatment (see section 4.2).
The potential for local immunosuppression (resulting in skin infections or cancers) is not known in the long term (i.e. over a number of years) (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. Cases of malignancies, including cutaneous neoplasms (e.g. cutaneous T-cell lymphomas) and other types of lymphomas, and skin carcinomas have been reported in patients using tacrolimus ointment (see section 4.8). Protopic should not be used in patients with congenital or acquired immunodeficiencies or in patients undergoing therapies that cause immunosuppression.
Protopic treated patients with atopic dermatitis showed no significant systemic concentrations of tacrolimus.
Lymphadenopathies reported in clinical trials were uncommon (0.8%). Most of these cases were related to infections (skin, respiratory tract, teeth) and resolved with "appropriate antibiotic therapy. Transplant patients treated with immunosuppressive therapy (eg systemic tacrolimus) have an increased risk of developing lymphomas; therefore, patients receiving Protopic who develop lymphadenopathy should be monitored to ensure that the lymphadenopathies resolve. Lymphadenopathy present at the time of initiation of therapy should be evaluated and monitored. "etiology. In the absence of a clear etiology of lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Protopic should be considered.
The effect of Protopic ointment treatment on the immune system development of children under 2 years of age has not been established (see section 4.1).
Protopic ointment has not been evaluated for its safety and efficacy in the treatment of infected atopic dermatitis. Before starting treatment with Protopic ointment, the infected areas must be treated. 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 herpeticus], herpes simplex [cold sores], Kaposi's varicelliform rash) (see section 4.8). In the presence of these infections, the balance of risk and benefit associated with the use of Protopic should be weighed.
Emollients cannot be applied to the same area within 2 hours before or after the application of Protopic ointment. The concomitant use of other topical preparations has not been studied. There is no experience with the concomitant use of systemic steroids or immunosuppressive agents.
Contact with eyes and mucous membranes should be avoided. If it is accidentally applied to these areas, the area should be cleaned carefully and / or rinsed with water.
The use of Protopic ointment in patients with occlusive dressings has not been studied. The use of occlusive dressings is not recommended.
As with all topical medicinal products, patients should wash their hands after application unless the hands are also within the area to be treated.
Tacrolimus is extensively metabolised in the liver and although blood concentrations following topical therapy are low, the ointment should be used with caution in patients with hepatic impairment (see section 5.2).
04.5 Interactions with other medicinal products and other forms of interaction
No topical drug interaction studies have been conducted with tacrolimus ointment.
Tacrolimus is not metabolised in human skin; this indicates that there are no potential percutaneous interactions, which could affect the metabolism of tacrolimus itself.
Tacrolimus, when available systemically, is metabolised by hepatic cytochrome P450 3A4 (CYP3A4). Systemic exposure following topical application of tacrolimus ointment is low (erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread disease and / or erythrodermal disease should be done with caution.
Pediatric population
An interaction study was conducted with the protein-conjugate vaccine against the subgroup C of the Neisseria meningitidisin children aged 2 to 11 years. There was no effect on the immediate response to the vaccine, on the generation of immune memory or on cell-mediated and humoral immunity (see section 5.1).
04.6 Pregnancy and lactation
Fertility
There are no data available on fertility.
Pregnancy
There are no adequate data from the use of tacrolimus ointment in pregnant women. Animal studies have shown reproductive toxicity after systemic administration (see section 5.3). The potential risk for humans is unknown.
Protopic ointment should not be used during pregnancy unless absolutely necessary.
Feeding time
Human data indicate that following systemic administration, tacrolimus is excreted in breast milk. Although clinical data have shown that systemic exposure due to application of tacrolimus ointment is minimal, breastfeeding is not recommended. period of treatment with Protopic ointment.
04.7 Effects on ability to drive and use machines
Protopic ointment has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
During clinical studies, approximately 50% of patients experienced some type of skin irritation in the application area as an adverse reaction. Burning and itching sensations are very common, usually mild to moderate in severity and with a tendency to resolve within one week of starting treatment. Another common adverse skin irritation reaction is erythema. They have also been commonly observed. in the area of application, sensation of heat, pain, paraesthesia and rash. Common is alcohol intolerance (facial flushing or skin irritation after the consumption of alcoholic beverages).
The risk of folliculitis, acne, and herpes viral infections could increase.
Adverse reactions suspected to be related to treatment are listed below and divided by organ and system classification. Frequencies are defined as very common (≥1 / 10), common (≥1 / 100,
* Adverse reactions were reported during postmarketing surveillance.
Post-marketing
Cases of malignancies, including cutaneous forms (e.g. cutaneous T-cell lymphomas) and other types of lymphomas, and skin carcinomas, have been reported in patients using tacrolimus ointment (see section 4.4).
Maintenance treatment
In a maintenance treatment study (twice weekly treatment) in adults and children with moderate and severe atopic dermatitis, the following adverse events were found 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).
Pediatric population
The frequency, type and severity of adverse reactions in children are similar to those reported for adults.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. in "Annex V.
04.9 Overdose
Overdose in topical application is unlikely.
If ingested, general supportive measures may be required, including monitoring of vital signs and observation of clinical status. Due to the nature of the ointment carrier, induction of vomiting and gastric lavage are not recommended.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 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 mechanisms of action have been observed, their clinical significance in atopic dermatitis is not known.
Through its binding to a specific cytoplasmic immunophylline (FKBP12), tacrolimus inhibits calcium-dependent signaling pathways in T lymphocytes, thus 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 healthy human skin, tacrolimus reduces stimulating activity towards T cells. Tacrolimus has been shown to inhibit the release of inflammatory mediators from cutaneous mast cells, basophils and eosinophils.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models, similar to human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, the improvement of skin lesions during treatment with tacrolimus ointment is associated with a reduced expression of Fc receptors on Langerhans cells and a reduction in their hyperstimulatory activity towards T cells. Tacrolimus ointment has no effect. on the synthesis of collagen in man.
Clinical efficacy and safety
Protopic has been evaluated for efficacy and safety in more than 18,500 patients treated with tacrolimus ointment in Phase I to III clinical trials. Data from the six main clinical studies are presented below.
In a randomized, double-blind, 6-month study, tacrolimus ointment 0.1% was applied twice daily to adults with moderate to severe atopic dermatitis and compared with a topical corticosteroid-based treatment ( 0.1% hydrocortisone butyrate on trunk and limbs, 1% hydrocortisone acetate on face and neck). The primary endpoint was the degree of response after three months, defined as the percentage of patients who had an improvement of at least 60% in mEASI (Modified Index of Severity and Area of Eczema) at month 3 from baseline. The degree of response in the 0.1% tacrolimus group (71.6%) was significantly greater than in the topical corticosteroid group (50.8%; p
Table 1 Efficacy at 3 months
§ treatment with topical corticosteroid = 0.1% hydrocortisone butyrate on the trunk and extremities, 1% hydrocortisone acetate on the face and neck
§ § higher values = greater improvement
The incidence and nature of most adverse events were similar in the two treatment groups. Burning of the skin, herpes simplex, alcohol intolerance (facial flushing or skin irritation after drinking alcohol), tingling sensation , hyperesthesia, acne and fungal dermatitis occurred more frequently in the tacrolimus group. There were no clinically relevant changes in laboratory values or vital signs in either treatment group over the course of the study.
In the second study, children aged 2-15 years with moderate to severe atopic dermatitis were treated, twice daily for three weeks, with 0.03% tacrolimus ointment, 0.1% tacrolimus ointment, or hydrocortisone acetate ointment. 1%. The primary endpoint throughout the study was the mean AUC (area under the curve) as a percentage of the mEASI score from baseline. The results of this multicentre, double-blind, randomized study demonstrated that tacrolimus ointment 0.03% and 0.1%, is significantly more effective (p
Table 2 Efficacy at the third week
§ lower values = greater improvement
The incidence of local skin burning was higher in the tacrolimus groups than in the hydrocortisone group. Pruritus decreased over time in the tacrolimus groups but not in the hydrocortisone group. There were no relevant clinical changes in the laboratory or vital signs values in each treatment group over the course of the study.
The objective of the third multicentre, double-blind, randomized study was the evaluation of the efficacy and safety of tacrolimus ointment 0.03% applied once or twice daily compared to the twice daily application of hydrocortisone acetate ointment 1%. in children with moderate to severe atopic dermatitis The duration of treatment was greater than three weeks.
Table 3 Efficacy at the third week
§ higher values = greater improvement
The primary endpoint was defined as the percentage decrease in mEASI from baseline to the end of treatment. Statistically significant improvement was observed with tacrolimus ointment 0.03% once or twice daily compared with hydrocortisone acetate ointment twice daily (p
In the fourth, open-label, long-term safety study, approximately 800 patients (age ≥2 years) received tacrolimus ointment 0.1% for up to four years, either intermittently or continuously, with 300 patients receiving received treatment for at least three years and 79 patients who received treatment for a minimum of 42 months. Based on the change from baseline in EASI score and affected body area, patients, regardless of age, showed improvement in their atopic dermatitis at all subsequent time points. Furthermore, there was no evidence of loss of efficacy throughout the duration of the clinical study.
The overall incidence of adverse events tended to decrease as the study progressed for all patients regardless of age. The three most common adverse events reported were flu-like symptoms (cold, cold, flu, upper respiratory tract infections, etc.), itching and burning of the skin. In this long-term study, no adverse events not reported in short-term studies and / or observed in previous studies were observed.
The efficacy and safety of tacrolimus ointment in the maintenance treatment of mild to severe atopic dermatitis was evaluated in 524 patients in two Phase III multicenter clinical trials of similar design in adult patients (≥16 years) and in adult patients, respectively. pediatric (2-15 years).
In both studies, patients with ongoing disease underwent an Open-Label Period (OLP) during which affected lesions were treated with tacrolimus ointment two for up to 6 weeks. times a day until the improvement reached a predetermined score (Investigator's Global Assessment - IGA ≤2, i.e. lesions disappeared, almost disappeared or present in a mild form). Thereafter, patients began a period of Double-blind control period (DCP) disease control for 12 months. Patients were randomized to receive tacrolimus ointment (0.1% for adults, 0.03% for children) or vehicle once a day twice a week, on Mondays and Thursdays.
Upon the occurrence of a disease flare, patients were treated open label with tacrolimus ointment twice daily for up to 6 weeks until the IGA score returned to ≤2.
The primary objective in both studies was to evaluate the number of disease exacerbations requiring "substantial therapeutic intervention" during the DCP period, defined as an exacerbation with an IGA of 3-5 (i.e. moderate, severe and very severe disease degree). severe) during the first day of the exacerbation, requiring more than 7 days of treatment. Both studies showed significant benefit with twice weekly treatment with tacrolimus ointment over key primary and secondary endpoints over a 12-month period. in a population of patients with mild to severe atopic dermatitis. In a population sub-analysis of patients with moderate to severe atopic dermatitis these differences remained statistically significant (Table 4). No events were observed in these studies. adverse not previously reported.
Table 4 Efficacy (moderate to severe subpopulation)
DE: Disease Exacerbation
P.
A 7-month, double-blind, randomized study was conducted in parallel groups of pediatric patients (2-11 years) with moderate to severe atopic dermatitis. In one arm, patients were treated with Protopic 0.03% ointment (n = 121) twice daily for 3 weeks and then once daily until lesions disappeared. In the control arm, patients were treated with 1% hydrocortisone acetate (HA) ointment for head and neck and 0.1% hydrocortisone butyrate ointment for trunk and limbs (n = 111) twice daily for 2 weeks and then with HA twice a day on all affected areas. During this period all patients and control subjects (n = 44) received a primary immunization and a booster with a protein-conjugated vaccine against subgroup C of the Neisseria meningitidis.
The primary endpoint of the study was the response rate to vaccination, defined as the percentage of patients with a serum bactericidal antibody (SBA) titer ≥8 at the week 5 visit. The "response rate analysis at week 5 showed a" equivalence between treatment groups (hydrocortisone 98.3%, tacrolimus ointment 95.4%; 7-11 years: 100% in both arms) Results in the control group were similar.
The primary response to vaccination was not affected.
05.2 Pharmacokinetic properties
Clinical data have demonstrated that tacrolimus concentrations in the systemic circulation following topical administration are minimal and, when measurable, transient.
Absorption
Data from healthy volunteers indicate that there is little or no systemic exposure to tacrolimus following single or repeated topical application of tacrolimus ointment.
Most patients (adults and children) treated for atopic dermatitis with one or more applications of tacrolimus ointment (0.03 - 0.1%) and infants from 5 months of age treated with tacrolimus ointment (0 , 03%) had treated body surface area blood concentrations, the systemic exposure (ie AUC) of tacrolimus from Protopic is approximately 30 times lower than that seen with an oral immunosuppressive dosage in liver or kidney transplant patients. The lowest blood concentration of tacrolimus with which the systemic effect can be observed is unknown.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for long periods (up to one year) with tacrolimus ointment.
Distribution
Due to the low systemic exposure of tacrolimus ointment, the high binding of tacrolimus (> 98.8%) to plasma proteins is not considered clinically relevant.
Following topical applications of tacrolimus ointment, tacrolimus is selectively released to the skin with minimal diffusion into the systemic circulation.
Metabolism
No metabolism of tacrolimus by human skin has been detected. Systemically available tacrolimus is predominantly metabolised in the liver by CYP3A4.
Elimination
In intravenous administration, tacrolimus was found to be a slow elimination rate drug.
The mean body clearance is approximately 2.25 l / h. The hepatic elimination of systemically available tacrolimus may be reduced in subjects with severe hepatic impairment, or in subjects who are treated concomitantly with drugs that are potent inhibitors of CYP3A4.
Following repeated local applications of the ointment, the mean half-life of tacrolimus was estimated to be 75 hours in adults and 65 hours in children.
Pediatric population
The pharmacokinetics of tacrolimus following topical application are similar to those reported in adults, with minimal systemic exposure and no evidence of accumulation (see above).
05.3 Preclinical safety data
Toxicity after repeated treatments and local tolerability
Repeated topical application of tacrolimus ointment or its vehicle to rats, rabbits and miniature pigs was found to be associated with mild skin changes such as erythema, edema and papules.
In rats, long-term topical treatment with tacrolimus led to a state of systemic toxicity, which involved alterations in the kidneys, pancreas, eyes and nervous system. The changes are due to the high exposure of rodents resulting from the high transdermal absorption of tacrolimus. The only systemic variation observed in dwarf pigs for high concentrations of ointment (3%) was a slightly lower weight gain in females.
Rabbits were shown to be particularly sensitive to intravenous administration of tacrolimus, as they exhibited reversible cardiotoxic effects.
Mutagenicity
The tests in vitro and in vivo did not indicate a genotoxic potential of tacrolimus.
Carcinogenicity
Systemic carcinogenicity studies in mice (18 months) and rats (24 months) did not reveal the existence of carcinogenic potentials of tacrolimus.
In the dermal carcinogenicity study, which lasted 24 months, performed in mice with the application of 0.1% ointment, no skin tumors occurred. In the same study, an increased incidence of lymphoma was observed. , associated with high systemic exposure.
As part of a photocarcinogenicity study, hairless albino mice were treated chronically with tacrolimus ointment and UV radiation. "increase in the number of tumors. It is not clear whether the effect of tacrolimus is due to a systemic immunosuppression or a local effect. A risk to humans cannot be completely excluded as the potential for local immunosuppression in long-term use of tacrolimus ointment is unknown.
Reproductive toxicity
Embryo / fetal toxicity was observed in rats and rabbits, but only at doses that produced significant maternal toxicity. Reduced sperm function was detected in male rats at high subcutaneous doses of tacrolimus.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
White petroleum jelly; liquid paraffin; propylene carbonate; white beeswax; solid paraffin.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Laminated tube with low density polyethylene inner lining, closed with white polypropylene screw cap.
Packs of 10 g, 30 g and 60 g. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Astellas Pharma Europe B.V. - Sylviusweg 62, 2333 BE Leiden - The Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/02/201/001 Protopic 0.03% - AIC: 035575012
EU / 1/02/201/002 Protopic 0.03% - AIC: 035575024
EU / 1/02/201/005 Protopic 0.03% - AIC: 035575051
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 28/02/2002
Renewal date: 11/20/2006
