LEO Pharma


Getz Bros
Full Prescribing Info
Pharmacology: 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 calcium-dependent signal transduction pathways in T cells, thereby preventing the transcription and synthesis of IL-2, IL-3, IL-4, IL-5 and other cytokines eg, GM-CSF, TNF-α and IFN-γ.
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.
In animals, tacrolimus ointment suppressed inflammatory reactions in experimental and spontaneous dermatitis models that resemble human atopic dermatitis. Tacrolimus ointment did not reduce skin thickness and did not cause skin atrophy in animals.
In patients with atopic dermatitis, improvement of skin lesions during treatment with tacrolimus ointment was associated with reduced Fc receptor expression on Langerhans cells and a reduction of their hyperstimulatory activity towards T cells. Tacrolimus ointment does not affect collagen synthesis in humans.
Pharmacokinetics: 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 (0.03-0.3%) had blood concentrations <1 ng/mL. When observed, blood concentrations exceeding 1 ng/mL were transient. Systemic exposure increases with increasing treatment areas. However, both the extent and rate of topical absorption of tacrolimus decrease as the skin heals. In both adults and children with an average of 50% body surface area treated, systemic exposure (ie, AUC) of tacrolimus from Protopic is approximately 30-fold less than that seen with oral immunosuppressive doses in kidney and liver transplant patients. The lowest tacrolimus blood concentration at which systemic effects can be observed is not known.
There was no evidence of systemic accumulation of tacrolimus in patients (adults and children) treated for prolonged periods (up to 1 year) with tacrolimus ointment.
Distribution: As systemic exposure is low with tacrolimus ointment, the high binding of tacrolimus (>98.8%) to plasma proteins is considered not to be clinically relevant.
Metabolism: Metabolism of tacrolimus by human skin was detectable. Systemically available tacrolimus is extensively metabolized in the liver via CYP3A4.
Elimination: When administered IV, tacrolimus has been shown to have a low clearance rate. The average total body clearance is approximately 2.25 L/hr. The hepatic clearance of systemically available tacrolimus could be reduced in subjects with severe hepatic impairment, or in subjects who are co-treated with drugs that are potent inhibitors of CYP3A4.
Following repeated topical application of the ointment the average half-life of tacrolimus was estimated to be 75 hrs for adults and 65 hrs for children.
Toxicology: Preclinical Safety Data: In chronic toxicity studies in rats up to 26 weeks, rabbits up to 28 days, or in micropigs up to 52 weeks, repeated topical administration of tacrolimus ointment or the ointment vehicle was associated with slight dermal changes eg, erythema, edema and papules. Tacrolimus ointment (0.03-3%) did not induce contact hypersensitivity or photosensitization in guinea pigs or cutaneous phototoxicity in albino hairless mice.
There was no evidence of mutagenic potential.
In a 24-month dermal carcinogenicity study performed in mice with 0.1% ointment, no skin tumors were observed. In the same study an increased incidence of lymphoma was detected in association with high systemic exposure.
In a photocarcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation exposure (40 weeks of treatment followed by 12 weeks of observation) with 0.1% tacrolimus ointment. Reproductive toxicology studies were not performed with topical tacrolimus. In studies of oral tacrolimus no impairment of fertility was seen in male and female rats.
Protopic 0.03% Ointment: Short and long-term treatment of atopic dermatitis in adults and children ≥2 years.
Protopic 0.1% Ointment: Short and long-term treatment of atopic dermatitis in adults.
Dosage/Direction for Use
Protopic should be applied as a thin layer to affected areas of the skin twice daily. Protopic may be used on any part of the body, including face, neck and flexure areas, except on mucous membranes. Protopic should not be applied under occlusion (see Precautions).
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 1 week of starting treatment. If no signs of improvement are seen after 2 weeks of treatment, further treatment options should be considered. Protopic can be used for short-term and intermittent long-term treatment.
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.
Hypersensitivity to macrolides in general, to tacrolimus or to any of the excipients of Protopic.
Special Precautions
Exposure of the skin to sunlight should be minimized 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 (see Toxicology under Actions). Physicians should advise patients on appropriate sun protection methods eg, minimization of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing.
Emollients should not be applied to the same area within 2 hrs of applying Protopic. Concomitant use of other topical preparations has not been assessed. There is no experience with concomitant use of systemic steroids or immunosuppressive agents.
Protopic 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 herpes simplex virus infection [including herpes, cold sores and eczema herpeticum (Kaposi's varicelliform eruption)]. In the presence of these infections, the balance of risks and benefits associated with Protopic use should be evaluated.
Beyond 2 years of treatment, the potential for local immunosuppression (possibly resulting in infections or cutaneous malignancies) is unknown.
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 (eg, systemic tacrolimus) are at an increased risk for developing lymphoma; therefore patients who receive Protopic and who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves. In case of persistent lymphadenopathy, the etiology of the lymphadenopathy should be investigated. In the absence of a clear etiology for the lymphadenopathy or in the presence of acute infectious mononucleosis, discontinuation of Protopic 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 Protopic 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 metabolized 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 Pharmacokinetics under Actions).
The use of Protopic in patients with genetic epidermal barrier defects eg, Netherton's syndrome is not recommended due to the potential for permanently increased systemic absorption of tacrolimus. The safety of Protopic has not been established in patients with generalized erythroderma.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects to drive or use machines have been performed. Protopic is administered topically and is unlikely to have an effect on the ability to drive or use machines.
Use in pregnancy & lactation: There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women. The experience with Protopic when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy. Protopic should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Although systemic absorption of tacrolimus following topical applications of Protopic is minimal relative to systemic administration, it is known that tacrolimus is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tacrolimus, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: The effect of treatment with Protopic on the developing immune system of children, especially the young, has not yet been established and this should be taken to account when prescribing to this age group (see Indications).
Controlled studies of Protopic in children were conducted involving patients 2-15 years. Documented use in patients <2 years old is limited.
Adverse Reactions
The use of Protopic may cause local symptoms eg, skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of Protopic application and typically improve as the lesions of atopic dermatitis heal. The local symptoms are usually mild or moderate in severity and are of limited duration. With Protopic 0.1%, 90% of the skin burning events had a median duration of 15 min. Ninety percent of the pruritus events had a mean duration of 20 min.
Adverse reactions with suspected relationship to treatment are listed below by body system. Frequencies are defined as: Very common (>1/10) and common (<1/100, <1/10).
Skin and Appendages: Very common: Burning skin, pruritus, skin erythema. Common: Tingling skin, folliculitis, acne, herpes simplex [herpes, cold sores, eczema herpeticum (Kaposi's varicelliform eruption)].
Nervous System: Common: Hyperesthisia (increased skin sensitivity, especially to hot and cold).
Body as a Whole: Common: Alcohol intolerance (facial flushing or skin irritation after consumption of an alcoholic beverage).
Drug Interactions
Formal topical drug interaction studies with tacrolimus ointment have not been conducted.
Tacrolimus is not metabolized in human skin, indicating that there is no potential for percutaneous interactions that could affect the metabolism of tacrolimus.
Systemically available tacrolimus is metabolized via the hepatic cytochrome P-450 3A4 (CYP3A4). Systemic exposure from topical application of tacrolimus ointment is low (<1 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 (eg, erythromycin, itraconazole, ketoconazole and diltiazem) in patients with widespread and/or erythrodermic disease should be done with caution.
A potential interaction between vaccination and application of Protopic has not been investigated. Because of the potential risk of vaccination failure, vaccination should be administered prior to commencement of treatment, or during a treatment-free interval with a period of 14 days between the last application of Protopic and the vaccination. In case of live attenuated vaccination, this period should be extended to 28 days or the use of alternative vaccines should be considered.
Store at temperatures not exceeding 25°C.
MIMS Class
Other Dermatologicals
ATC Classification
D11AH01 - tacrolimus ; Belongs to the class of agents for atopic dermatitis, excluding corticosteroids. Used in the treatment of atopic dermatitis.
Oint 0.03% x 10 g. 0.1 % x 10 g.
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