Tacrolimus 0.1 % Ointment is indicated in adults and adolescents (16 years of age and
above).
Flare treatment
Adults and adolescents (16 years of age and above)
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
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).

 

Tacrolimus treatment should be initiated by physicians with experience in the diagnosis
and treatment of atopic dermatitis. Tacrolimus is available in two strengths, Tacrolimus
0.03 % and Tacrolimus 0.1 % Ointment.
Posology Flare treatment
Tacrolimus can be used for short-term and intermittent long-term treatment. Treatment
should not be continuous on a long- term basis.
Tacrolimus treatment should begin at the first appearance of signs and symptoms. Each
affected region of the skin should be treated with Tacrolimus until lesions are cleared,
almost cleared or mildly affected. Thereafter, patients are considered suitable for
maintenance treatment. At the first signs of recurrence (flares) of the disease symptoms,
treatment should be re-initiated.
Adults and adolescents (16 years of age and above)
Treatment should be started with Tacrolimus 0.1% twice a day and treatment should be

continued until clearance of the lesion. If symptoms recur, twice daily treatment with
Tacrolimus 0.1% should be restarted. An attempt should be made to reduce the
frequency of application or to use the lower strength Tacrolimus 0.03% ointment if the
clinical condition allows.
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.
Older people
Specific studies have not been conducted in older people. However, the clinical
experience available in this patient population has not shown the necessity for any
dosage adjustment.
Paediatric population
Only Tacrolimus 0.03 % ointment should be used in children from the age of 2 to 16
years.
Tacrolimus ointment should not be used in children aged below 2 years until further
data are available.
Maintenance treatment
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.
Adults and adolescents (16 years of age and above)
Adult patients (16 years of age and above) should use Tacrolimus 0.1% ointment.
Tacrolimus 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 2–3 days without Tacrolimus treatment.
After 12 months treatment, 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.
If signs of a flare reoccur, twice daily treatment should be re-initiated.
Older people
Specific studies have not been conducted in older people.

Paediatric population
Only Tacrolimus 0.03 % ointment should be used in children from the age of 2 to 16
years.
Tacrolimus ointment should not be used in children aged below 2 years until further
data are available.
Method of administration
Tacrolimus ointment should be applied as a thin layer to affected or commonly
affected areas of the skin. Tacrolimus ointment may be used on any part of the body,
including face, neck and flexure areas, except on mucous membranes. Tacrolimus
ointment should not be applied under occlusion because this method of administration
has not been studied in patients.

Route of Administration: Topical

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 Tacrolimus ointment. 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. Tacrolimus 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 Tacrolimus to patients with extensive skin
involvement over an extended period of time, especially in children.
Patients, particularly paediatric patients should be continuously evaluated during
treatment with Tacrolimus with respect to the response to treatment and the continuing
need for treatment. After 12 months this evaluation should include suspension of
Tacrolimus treatment in paediatric patients.
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.
Tacrolimus 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.
Tacrolimus 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 Tacrolimus 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 Tacrolimus 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 Tacrolimus should be
considered.
Tacrolimus ointment has not been evaluated for its efficacy and safety in the treatment
of clinically infected atopic dermatitis. Before commencing treatment with Tacrolimus
ointment, clinical infections at treatment sites should be cleared. Patients with atopic
dermatitis are predisposed to superficial skin infections. Treatment with Tacrolimus 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). In the presence of these infections, the balance of risks and
benefits associated with Tacrolimus use should be evaluated.
Emollients should not be applied to the same area within 2 hours of applying
Tacrolimus 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 Tacrolimus 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.

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 P4503A4
(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.

Fertility
There are no fertility data available.
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.
The potential risk for humans is unknown.
Tacrolimus 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
Tacrolimus ointment is not recommended.

Tacrolimus ointment has no or negligible influence on the ability to drive or 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.

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.

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).
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.
To report any side effect(s):
Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll Free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
Other GCC states: Please contact the relevant competent authority.

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.

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 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 such as GMCSF,
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.
Clinical efficacy and safety
The efficacy and safety of Tacrolimus was assessed in more than 18,500 patients treated
with tacrolimus ointment in Phase I to Phase III clinical trials. Data from six 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). The response rates at month 6 were comparable to the 3-
month results.

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).

§ 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.

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.
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 (Investigator's 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.

A seven-month, double blind, randomised parallel group study of paediatric patients (2-
11 years) with moderate to severe atopic dermatitis was performed. In one arm
patients received Tacrolimus 0.03% ointment (n=121) twice a day for 3 weeks and
thereafter once a day until clearance. In the comparator arm patients received 1%
hydrocortisone acetate ointment (HA) for head and neck and 0.1% hydrocortisone
butyrate ointment for trunk and limbs (n=111) twice a day for 2 weeks and
subsequently HA twice a day to all affected areas. During this period all patients and
control subjects (n=44) received a primary immunisation and a rechallenge with a
protein-conjugate vaccine against Neisseria menigitidis serogroup C.
The primary endpoint of this study was the response rate to vaccination, defined as the
percentage of patients with a serum bactericidal antibody (SBA) titre ≥ 8 at the week 5
visit. Analysis of the response rate at week 5 showed equivalence between the treatment
groups (hydrocortisone 98.3%, tacrolimus ointment 95.4%; 7-11 years: 100% in both
arms). The results in the control group were similar.

The primary response to vaccination was not affected.

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 ointment (0.03%) had blood concentrations < 1.0 ng/ml. When
observed, blood concentrations exceeding 1.0 ng/ml were transient. Systemic exposure
increases with increasing treatment areas. However, both the extent and the 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 (i.e. AUC) of
tacrolimus from Tacrolimus 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 one 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.
Following topical application of tacrolimus ointment, tacrolimus is selectively delivered
to the skin with minimal diffusion into the systemic circulation.
Metabolism
Metabolism of tacrolimus by human skin was not detectable. Systemically available
tacrolimus is extensively metabolised in the liver via CYP3A4.
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 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 hours for adults and 65 hours for children.
Paediatric population
The pharmacokinetics of tacrolimus after topical application are similar to those
reported in adults, with minimal systemic exposure and no evidence of accumulation.

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
significant toxicity in maternal animals. Reduced sperm function was noted in male
rats at high subcutaneous doses of tacrolimus.

Not applicable

Store below 30°C.

NOT FOR CHILDREN.

A printed carton containing a leaflet and a printed lami tube containing white to
yellow semi-solid ointment.

No special requirements