ELIDEL CREAM 1 %

יפל ןכרצל ןולע םיחקורה תונקת

םירישכת

משתה

"

1986

אפור םשרמב תבייח וז הפורת

ארק

שמתשת םרטב ופוס דע ןולעה תא ןויעב י

הפורתב י

םרק לדילא

1%

בכרה

לכ

ליכמ םרק םרג

Pimecrolimus 10 mg

םיליעפ יתלב םירמוח

Triglycerides, oleyl alcohol, propylene glycol, stearyl alcohol, cetyl alcohol, mono – and di-

glycerides, sodium cetostearly sulphate, benzyl alcohol, citric acid, sodium hydroxide,

purified water.

תיאופר תוליעפ

:

לדילא

יבכעמ תצובקמ תופורתל ךיישו רועה לש תקלדב לפטמה דיאורטס וניאש רישכת וניה םרק ןירואניצלק םייחטש

דוריגהו תוימומדאלו תקלדל םימרוג רשא רועה לש םיאתב לעופ רישכתה המזקאל םיינייפואה

ב לופיטל דעוימ רועה לע שומישב רישכתה

atopic dermatitis

המזקא

תוקוניתב

ליגמ

הלעמו םישדוח

םידלי

לפטל ןתינ אלש וא וביגה אלש םירגובמו םירגבתמ דיאורטסוקיטרוקב םהב רועה לע םי

יתמ ןיא רישכתב שמתשהל

?

יחרמת לא לדילא

הקינימ ךניה םא הזחה רוזיא לע

דחאל תושיגר ךל העודי םא שמתשהל ןיא הפורתה יביכרממ

ינפל אפורב ץעוויהל ילבמ הפורתב שמתשהל ןיא חתה לופיטה תל

ןוירהב ךניהש תבשוח תא םא וא ןוירהב ךניה םא

נכנ םא אפורל עידוהל שי רישכתב שומישה ךלהמב ןוירהל תס

הקינימ ךניה םא

ב ליעפה רמוחה םא עודי אל לדילא

רועה לע החירמ רחאל םאה בלחל רבוע

רועב םוהיז ךל שי םא

ה םא לבוס ךני

ןוסיחה תכרעמב יוקילמ ת

לבוס ךניה םא

תיפוליק רוע תקלדמ וא ןוטרתנ תנומסתמ ת

generalized erythroderma

תומדאתה ףוגה רוע לכ לש תיתקלד

תורהזא

:

שרנ המשלש וזמ הנוש הרטמל רישכתב שמתשהל ןיא

העודי הניא ךורא ןמזל שומישב תוחיטבהש תויה ךשוממ ןמזל תופיצרב רישכתב שמתשהל ןיא

םירידנ םירקמב

ןטרסב ולח םילפוטמ

המופמיל וא רועה ןטרס לשמל

יבכעמ םע לופיט ךלהמב מוקמ ןירואניצלק

םיללוכה ם לדילא

יבכעמב שומישל הלחמה ןיב יתביס רשק חכוה אל תאז םע םיימוקמ ןירואניצלק

ןיא

חורמ לדילא

ינטרס לודיגכ םידושחה רועב םיעצפ לע

חוטב ךניא םא אפורה םע אדוול שי

ךכב

חורמל ןיא לדילא

א לע ילאריו םוהיזב םיעוגנה רועב םירוז

ספרה לשמל

והיז לש הרקמב רועב ם

לפטמה אפורל תונפל שי

םוהיזב לפטל ךירצ םדוקש ןכתי

יתוכאלמ וא יעבט שמש רואל רועה תפישחמ ענמיהל שי

ףוזיש תורונמ ללוכ

וא ףוזיש תוטימ לוגס הרטלוא רואב לופיט

תחירמ רחאל ץוחב ההוש ךניה םא לדילא

הנגה םרקב שמתשהל ךילע מ רועה לע ןגמה דומצ אל דגב שובללו שמשה ינפ

ךלהמב שמשל הפישחה ןמז תא םצמצל שי ב לופיטה לדילא

רועה לע חורמ אל םרקהשכ םג

ףסונב

תופסונ םיכרד יבגל אפורב ץעוויהל שי שמשהמ הנגהל

םירמוח ליכמ רישכתה

ןוגכ

cetyl alcohol, propylene glycol, stearyl alcohol

םילולעה יוריגל וא תוימוקמ תובוגתל םורגל

רועב

תוינמז תונותמ תובוגתל םורגל לולע רישכתב שומישה

הבירצ וא םוח תשגרה ןוגכ

רועה יוריגל וא

םדואו דוריג לשמל

החירמה רוזאב

חוודל שי םירומח םינימסתהש הדימב אפורל

יוריגל םורגל הלולע םיעצפ לע רישכתה תחירמ

םרקב לוהוכלאה תלוכת בקע

בוגת תו

יתפורת ןיב

ו

ת

:

נ ךניה םא

לט

תפסונ הפורת ת

םא וא תרחא הפורתב לופיט התע הז תרמג

אפורל חוודל ךילע וכיס עונמל ידכ לפטמה ינ יא וא ם

ןיב תובוגתמ םיעבונה תוליעי

תויתפורת

ןוסיח תלביקש הדימב חאל ור הנ

חורמל ןיא לדילא

ו תוימומדאה גופתש דע ןוסיחה תלבק םוקמ לע

תוחיפנה וא

ופ רישכתה לס ןפואב לע

םדה רוזחמל תגפסנ ליעפה רמוחה לש דואמ הנטק תומכו רועה לע יביט

ןיבה תובוגתה תושחרתמ ובש

תויתפורת

ןכל

תופורת ןיבל רישכתה ןיב תובוגתל תוריבסה הכומנ הניה הפה ךרד תוחקלנה תורחא

יאוול תועפות

הפורתה לש היוצרה תוליעפל ףסונב

תולולע הב שומישה ןמזב

יאוול תועפות עיפוהל

ו םוח תשגרה הניה רתויב החיכשה יאוולה תעפות

םרקה תחירמ רוזאב הבירצ וא

תוחיכש יאוול תועפות

יוריג

םרקה תחירמ רוזאב תוימומדאו דוריג

קלד

ןוגכ רועב ת ילופ סיטילוק

עישה יקיקזב תקלד תויתלגומל םורגל היושעש ר

תוחיכש אל יאוול תועפות

הרמחה לופיטה דעוימ ורובעש בצמב

תפעס ןוגכ יקדייח רוע םוהיז

(impetigo)

סקלפמיס ספרה ןוגכ םייפיגנ רוע ימוהיז

הטושפ תקבלש

רועב תוכיכר

molluscum contagiosum

סקלפמיס ספרהה ףיגנמ האצותכ רועב תקלד

(eczema

herpeticum)

החירפ

באכ

וצקע תשוחת

םישקשק תורצוויה

בוי תחירמ רוזאב תוחיפנו ש םרקה

תולבי

םביבסמ תומקרהו רעישה יקיקזב םוהיז

תויתלגומ תוסרומ

תונותמ ללכ ךרדב ןה הלא יאוול תועפות

לופיטה לש םדקומ בלשב תועיפומו תוינמז

תופסונ יאוול תועפות

שאר באכ

שודג ףא וא תוררקתה

ןורג באכ

תעפש

םוח

ילאריו םוהיז לועישו

ןוגכ רועב םיילאריו םימוהיז

רוק יעצפ

חור תועובעבא

ב לופיטל ליבקמב לוהוכלא םיכרוצש םילפוטמב תורידנ םיתיעל לדילא

,

תועפות שחרתהל תולולע רועב םייוריג וא םינפה רוזאב הקמסה לש יאוול

ןוגכ

החירפ

הבירצ תשוחת

תוחיפנ וא דרג

תורידנ םיתיעל

רועה עבצב יוניש שחרתהל לולע

רועהמ רתוי ריהב וא רתוי ההכ ךפוה רועה ביבסמש

םירידנ םירקמב

ןטרסב ולח םילפוטמ

המופמיל וא רועה ןטרס לשמל

לופיטה ךלהמב

לדילא

תאז םע

ב לופיטל הלחמה ןיב יתביס רשק חכוה אל לא לדי

תדחוימ תוסחייתה תובייחמה יאוול תועפות

ל היגרלא ןכתית םירידנ םירקמב לדילא

נל םורגת רשא יפ באכו תוח

תדפרס וא רועב החירפ

ףוצפצ ןוגכ םינימסתב אטבתהלו הרומח תויהל הלולע תיגרלאה הבוגתה דואמ םירידנ םירקמב ץחל תשוחת וא הזחב באכו ימואתפ המישנ

םייפעפעה תוחיפנ

םייתפשה וא םינפה

שיגרמ ךניה םא

ב שומישה רחאל הלא םינימסתמ דחאב ה לדילא

קספה

הנפו שומישה תא י

דימ אפורל

טמה אפורה תא עדייל שי

ב שומישה ךלהמב תוחפנתמ הפמילה תוטולב םא ל לדילא

ה ובש הרקמ לכב שיגרמ ךני

וצ אלש יאוול תועפות ה הז ןולעב וני

רהב יוניש לח םא וא ךתשג תיללכה

דימ אפורה םע ץעייתהל ךילע

אפורמ תרחא הארוה רדעהב לבוקמ ןונימ

םויב םיימעפ םרקה תא חורמל שי

ברעבו רקובב

לעיה םע

לש םימוטפמיסהו םינמיסה תו

atopic dermatitis

המזקא

לופיטה תא קיספהל שי

לדילא

ב שמתשהל רוזחל שי לדילא

ינמיסה לש תשדוחמ העפוה םע םימוטפמיסהו ם

ב שומיש ליחתהל שי חווט ךורא לופיטב דילא

ל

המזקאל םינמיסה תעפוה םע דימ

עונמל ידכ הלחמה לש הרומח תוצרפתהו םינימסתה לש תוחתפתה

ךות בצמב רופיש לח אל םא

תועובש

תינש אפורל תונפל שי

םיתיעל

תוארנ תורחא רוע תולחמ המזקא ומכ

ז הפורת חורמל תחכש םא בוצק ןמזב ו

םינמזב חורמל ךישמהלו תרכזנשכ דימ הנמ חורמל שי םיעובקה

ךירצשמ הלודג תומכ תועטב תחרמ םא

בגנ

תפדועה תומכה תא י

םיש

/

בל י

:

עולבל אל

הפורתהמ תעלבש הדימב

עדוה

לפטמה אפורל י

דילא

ל

דבלב ינוציח שומישל דעונ

ףאה ךותב ותוא חורמל ןיא

הפה וא םייניעה

הלא םירוזאב םרקה חרמנ תועטב םא

בגנל שי םייקנ םימב בטיה ףוטשלו ודירוהל תנמ לע בטיה

תועטב הפל םרקה תא סינכהל וא עולבל אלש בל םישל שי

םיידיה לע םרקה חרמנ רשאכ לשמל

אה תא תוסכל ןיא תמטוא השיבחב לפוטמה רוז

שומישה ןפוא

:

רועה ירוזא לכב םרקה תא חורמל ןתינ

שארה ללו

םינפה

רועה ילפקו ראווצה

תא חורמל שי המזקאב עוגנה רוזאב קרו ךא רועה לע רישכתה

רישכתב לופיטה רחאל המזקאל םינימסתה לש תשדוחמ העפוה לש הרקמב

אפורב ץעוויהל שי לפטמה

אבה ןפואב םרקב שמתשהל שי

ףוטש

שבייו י

םיידיה תא י

חתפ

תרפופשה תא י

נושארה םעפב חתפת הב ה

תרפופשה תא י

םתוחה תא חותפל שי קקפה הצקבש הטילבב שומיש ךות

ץחל

אצוהו תרפופשה לע י

ךעבצא לע םרק י

חרמ

ולוכ הסוכי עוגנה רוזאהש ךכ םרקה לש הקד הבכש י

הסע

םרקה לש האלמ הרדחהל דע תונידעב רועה תא י

רוגס

תרפופשה תא הרזחב י

ץחר

מה רחאל םיידיה תא החיר

םרקב תולפוטמ ןה םא אלא

םרקב שומישה רחאל דימ תוחל םרק חורמל ןתינ לדילא

לבא

הצחרה רחאל

םרק חורמל שי ב שומישה ינפל תוחל לדילא

לכות דציכ

/

לופיטה תחלצהל עייסל י

?

לע ץלמוהש לופיטה תא םילשהל ךילע

ידי

אפורה

לופיטה תא קיספהל שי יופיר גשוה םא

U

ענמ

/

רה י הלע

!

ו םידלי לש םדי גשיהל ץוחמ רוגס םוקמב רומשל שי תרחא הפורת לכו וז הפורת

לעו תוקונית וא

ענמת ךכ ידי

הלערה י

הפורתה ןמ דלי עלב תועטב םא וא רתי תנמ תלטנ םא

הנפ

תיב לש ןוימ רדחל דימ י

םילוח

אבהו

ךתיא הפורתה תזירא י

U

האקהל םורגל ןיא

U

אפורמ תשרופמ הארוה אלל

ךתלחמב לופיטל המשרנ וז הפורת

רחא הלוחב

קיזהל הלולע איה ת

ןתית לא

/

וז הפורת י ךיבורקל

,

ךירכמ וא ךינכש

.

U

ךשוחב תופורת לוטיל ןיא

U

הנמהו תיוותה תא קודבל שי

U

םעפ לכב

U

לטונ ךניהש

הפורת ת

שי קוקז ךניה םא םייפקשמ ביכרהל

םהל ה

הנסחא

איפקהל אל

ל תחתמ ןסחאל

תירוקמה הזיראב רומשל שי

שי רקב תרפופשה רומשל

ןו

הרוגס תרפופשה רומשל שי

החתפנ תרפופשהש עגרמ

ךות הב שמתשהל ןתינ

םישדוח

הזיראה יאנת יפל םג

םיצלמומה הנסחאה

דבלב תלבגומ הפוקתל תורמשנ תופורת

בל םישל אנ רישכתה לש הגופתה ךיראתל

קפס לש הרקמ לכב

ל ךילע הפורתה תא ךל קפיסש חקורב ץעוויה

תונוש תופורת ןסחאל ןיא הזירא התואב

סמ

'

הפורתה םושיר

30517

ןרצי

עב ןשקדורפ המראפ סיטרבונ

"

הינמרג

רובע עב המראפ הדמ

"

הינמרג

םושירה לעב

עב םראפאגמ

"

ןורשה דוה

45105

ע עבקנ הז ןולע טמרופ

"

דרשמ י רבמטפסב רשואו קדבנ ונכותו תואירבה

2009

ELI PIL 082011 P.1

ע עבקנ הז ןולע טמרופ

"

רבמטפסב ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י

Elidel

®

(pimecrolimus) Cream 1%

FOR DERMATOLOGIC USE ONLY

NOT FOR OPHTHALMIC USE

Rx only

Prescribing Information

DESCRIPTION

Elidel

(pimecrolimus) Cream 1% contains the compound pimecrolimus, the

immunosuppressant 33-epi-chloro-derivative of the macrolactam ascomycin.

Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-

12-[(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-

1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-

tricyclo[22.3.1.0

]octacos-18-ene-2,3,10,16-tetraone.

The compound has the empirical formula C

CINO

and the molecular weight of

810.47. The structural formula is:

Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol

and ethanol and insoluble in water.

Each gram of Elidel Cream 1% contains 10 mg of pimecrolimus in a whitish cream

base of benzyl alcohol, cetyl alcohol, citric acid, mono- and di-glycerides, oleyl

alcohol, propylene glycol, sodium cetostearyl sulphate, sodium hydroxide, stearyl

alcohol, triglycerides, and water.

CLINICAL PHARMACOLOGY

Mechanism of Action/Pharmacodynamics

The mechanism of action of pimecrolimus in atopic dermatitis is not known. While

the following have been observed, the clinical significance of these observations in

atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with

high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent

phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking

the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar

concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and

Interleukin-10 (Th2-type) cytokine synthesis in human T cells. In addition,

pimecrolimus prevents the release of inflammatory cytokines and mediators from

mast cells in vitro after stimulation by antigen/IgE.

Pharmacokinetics

Absorption

In adult patients (n=52) being treated for atopic dermatitis [13%-62% Body Surface

Area (BSA) involvement] for periods up to a year, a maximum pimecrolimus

concentration of 1.4 ng/mL was observed among those subjects with detectable blood

levels. In the majority of samples in adult (91%; 1244/1362) subjects, blood

concentrations of pimecrolimus were below 0.5 ng/mL. Data on blood levels of

pimecrolimus measured in pediatric patients are described below in

Special

Populations, Pediatrics

Distribution

Laboratory

in vitro

plasma protein binding studies using equilibrium gel filtration

have shown that 99.5% of pimecrolimus in plasma is bound to proteins over the

pimecrolimus concentration range of 2-100 ng/ml tested. The major fraction of

pimecrolimus in plasma appears to be bound to various lipoproteins.

As with other topical calcineurin inhibitors, it is not known whether pimecrolimus is

absorbed into cutaneous lymphatic vessels or in regional lymph nodes.

Metabolism

Following the administration of a single oral radiolabeled dose of pimecrolimus

numerous circulating O-demethylation metabolites were seen. Studies with human

liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A

sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism

was identified in vivo using the minipig or in vitro using stripped human skin.

Elimination

Based on the results of the aforementioned radiolabeled study, following a single oral

dose of pimecrolimus ~81% of the administered radioactivity was recovered,

primarily in the feces (78.4%) as metabolites. Less than 1% of the radioactivity found

in the feces was due to unchanged pimecrolimus.

Special Populations

Pediatrics

The systemic exposure to pimecrolimus from Elidel

(pimecrolimus) Cream 1% was

investigated in 28 pediatric patients with atopic dermatitis (20%-80% BSA

involvement) between the ages of 8 months-14 yrs. Following twice daily application

for three weeks, blood concentrations of pimecrolimus were <2 ng/mL with 60%

(96/161) of the blood samples having blood concentration below the limit of

quantification (0.5 ng/mL). However, the children (23 children out of the total 28

children investigated) had at least one detectable blood level as compared to the adults

(12 adults out of the total 52 adults investigated) over a 3-week treatment period. Due

to the erratic nature of the blood levels observed, no correlation could be made

between amount of cream, degree of BSA involvement, and blood concentrations. In

general, the blood concentrations measured in adult atopic dermatitis patients were

comparable to those seen in the pediatric population.

In a second group of 30 pediatric patients aged 3 to 23 months with 10%-92% BSA

involvement, following twice daily application for three weeks, blood concentrations

of pimecrolimus were <2.6 ng/mL with 65% (75/116) of the blood samples having

blood concentration below 0.5ng/mL, and 27% (31/116) below the limit of

quantification (0.1 ng/mL) for these studies.

Overall, a higher proportion of detectable blood levels was seen in the pediatric

patient population as compared to adult population. This increase in the absolute

number of positive blood levels may be due to the larger surface area to body mass

ratio seen in these younger subjects. In addition, a higher incidence of upper

respiratory symptoms/infections was also seen relative to the older age group in the

PK studies. At this time a causal relationship between these findings and Elidel use

cannot be ruled out.

Renal Insufficiency

The effect of renal insufficiency on the pharmacokinetics of topically administered

pimecrolimus has not been evaluated but dose-adjustment is not expected to be

needed as 80% of the drug is excreted in the feces.

Hepatic Insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of topically administered

pimecrolimus has not been evaluated but dose-adjustment is not expected to be

needed.

CLINICAL STUDIES

Three randomized, double-blind, vehicle-controlled, multi-center, Phase 3 studies

were conducted in 589 pediatric patients ages 3 months -17 years old to evaluate

Elidel

(pimecrolimus) Cream 1% for the treatment of mild to moderate atopic

dermatitis. Two of the three trials support the use of Elidel Cream in patients 2 years

and older with mild to moderate atopic dermatitis (see

PRECAUTIONS, Pediatric

Use

). Three other trials in 1619 pediatric and adult patients provided additional data

regarding the safety of Elidel Cream in the treatment of atopic dermatitis. Two of

these other trials were vehicle-controlled with optional sequential use of a medium

potency topical corticosteroid in pediatric patients and one trial was an active

comparator trial in adult patients with atopic dermatitis (see

PRECAUTIONS,

Pediatric Use

ADVERSE REACTIONS

Two identical 6-week, randomized, vehicle-controlled, multi-center, Phase 3 trials

were conducted to evaluate Elidel Cream for the treatment of mild to moderate atopic

dermatitis. A total of 403 pediatric patients 2-17 years old were included in the

studies. The male/female ratio was approximately 50% and 29% of the patients were

African American. At study entry, 59% of patients had moderate disease and the

mean body surface area (BSA) affected was 26%. About 75% of patients had atopic

dermatitis affecting the face and/or neck region. In these studies, patients applied

either Elidel Cream or vehicle cream twice daily to 5% to 96% of their BSA for up to

6 weeks. At endpoint, based on the physician’s global evaluation of clinical response,

35% of patients treated with Elidel Cream were clear or almost clear of signs of atopic

dermatitis compared to only 18% of vehicle-treated patients. More Elidel patients

(57%) had mild or no pruritus at 6 weeks compared to vehicle patients (34%). The

improvement in pruritus occurred in conjunction with the improvement of the

patients’ atopic dermatitis.

In these two 6-week studies of Elidel, the combined efficacy results at endpoint are as

follows:

In the two pediatric studies that independently support the use of Elidel Cream in mild

to moderate atopic dermatitis, a significant treatment effect was seen by day 15. Of

the key signs of atopic dermatitis, erythema, infiltration/papulation, lichenification,

and excoriations, erythema and infiltration/papulation were reduced at day 8 when

compared to vehicle.

The following graph depicts the time course of improvement in the percent body

surface area affected as a result of treatment with Elidel Cream in 2-17 year olds.

The following graph shows the time course of improvement in erythema as a result of

treatment with Elidel Cream in 2-17 year olds.

INDICATIONS AND USAGE

Elidel 1 % cream is indicated for the short-term treatment of the signs and symptoms

of atopic dermatitis (eczema) and intermittent long-term treatment to prevent

progression to flares in patients 3 months of age and above. Treatment with Elidel is

indicated in patients in whom the use of conventional topical corticosteroids therapy

is deemed inadvisable because of potential risks or in patients who are not adequately

responsive to or intolerant of conventional topical corticosteroids therapy.

CONTRAINDICATIONS

Elidel

(pimecrolimus) Cream 1% is contraindicated in individuals with a history of

hypersensitivity to pimecrolimus or any of the components of the cream.

WARNINGS

Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established

Although a causal relationship has not been established, rare cases of malignancy

(e.g., skin and lymphoma) have been reported in patients treated with topical

calcineurin inhibitors, including Elidel Cream.

Therefore:

Continuous long-term use of topical calcineurin inhibitors, including Elidel Cream, in

any age group should be avoided, and application limited to areas of involvement with

atopic dermatitis.

Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in

animal studies and transplant patients following systemic administration has been

associated with an increased risk of infections, lymphomas, and skin malignancies.

These risks are associated with the intensity and duration of immunosuppression.

Based on this information and the mechanism of action, there is a concern about a

potential risk with the use of topical calcineurin inhibitors, including ELIDEL Cream.

While a causal relationship has not been established, rare cases of skin malignancy

and lymphoma have been reported in patients treated with topical calcineurin

inhibitors, including Elidel Cream. Therefore:

Elidel Cream should not be used in immunocompromised adults and children.

If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients

should be re-examined by their healthcare provider and their diagnosis be confirmed

(see PRECAUTIONS).

The safety of Elidel Cream has not been established beyond one year of non-

continuous use.

(See

CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS,

INDICATIONS AND USAGE,

DOSAGE AND ADMINISTRATION

PRECAUTIONS

General

The use of Elidel Cream should be avoided on malignant or pre-malignant skin

conditions. Malignant or pre-malignant skin conditions, such as cutaneous T-cell

lymphoma (CTCL), can present as dermatitis.

Elidel Cream should not be used in patients with Netherton’s Syndrome or other skin

diseases where there is the potential for increased systemic absorption of

pimecrolimus

.

The safety of Elidel Cream has not been established in patients with

generalized erythroderma.

The use of Elidel Cream may cause local symptoms such as skin burning (burning

sensation, stinging, soreness) or pruritus. Localized symptoms are most common

during the first few days of Elidel Cream application and typically improve as the

lesions of atopic dermatitis resolve (see

ADVERSE REACTIONS

Bacterial and Viral Skin Infections

: Before commencing treatment with Elidel

Cream, bacterial or viral infections at treatment sites should be resolved. Studies have

not evaluated the safety and efficacy of Elidel Cream in the treatment of clinically

infected atopic dermatitis.

While patients with atopic dermatitis are predisposed to superficial skin infections

including eczema herpeticum (Kaposi’s varicelliform eruption), treatment with Elidel

Cream may be independently associated with an increased risk of varicella zoster

virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema

herpeticum.

In clinical studies, 15/1544 (1%) cases of skin papilloma (warts) were observed in

patients using Elidel Cream. The youngest patient was age 2 and the oldest was age

12. In cases where there is worsening of skin papillomas or they do not respond to

conventional therapy, discontinuation of Elidel Cream should be considered until

complete resolution of the warts is achieved.

Patients with Lymphadenopathy

: In clinical studies, 14/1544 (0.9%) cases of

lymphadenopathy (0.9%) were reported while using Elidel Cream. These cases of

lymphadenopathy were usually related to infections and noted to resolve upon

appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear

etiology or were known to resolve. Patients who receive Elidel Cream and who

develop lymphadenopathy should have the etiology of their lymphadenopathy

investigated. In the absence of a clear etiology for the lymphadenopathy, or in the

presence of acute infectious mononucleosis, Elidel Cream should be discontinued.

Patients who develop lymphadenopathy should be monitored to ensure that the

lymphadenopathy resolves.

Sun Exposure

: During the course of treatment, it is prudent for patients to minimize

or avoid natural or artificial sunlight exposure, even while Elidel is not on the skin.

The potential effects of Elidel Cream on skin response to ultraviolet damage are not

known.

Immunocompromised Patients

: The safety and efficacy of Elidel Cream in

immunocompromised patients have not been studied.

Information for Patients

Patients using Elidel should receive the following information and instructions:

What is the most important information a patient should know about Elidel

Cream?

The safety of using Elidel Cream for a long period of time is not known. A very small

number of people who have used Elidel Cream have had cancer (for example, skin or

lymphoma). However, a link with Elidel Cream use has not been shown. Because of

this concern:

A patient should not use Elidel Cream continuously for a long time.

Elidel Cream should be used only on areas of skin that have eczema.

How should a patient use Elidel Cream?

A patient should use Elidel Cream exactly as prescribed.

A patient should use Elidel Cream only on areas of skin that have eczema.

A patient should use Elidel Cream for short periods, and if needed, treatment may be

repeated with breaks in between.

A patient should stop Elidel Cream when the signs and symptoms of eczema, such

as itching, rash, and redness go away, or as directed by the physician.

A patient should follow the physician’s advice if symptoms of eczema return after a

treatment with Elidel Cream.

A patient should contact the physician if:

symptoms get worse with Elidel Cream

the patient gets a skin infection

symptoms do not improve after 6 weeks of treatment.

To apply Elidel Cream:

A patient or caregiver should wash their hands before using Elidel Cream. When

applying Elidel Cream after a bath or shower, the skin should be dry.

A patient or caregiver should apply a thin layer of Elidel Cream only to the affected

skin areas, twice a day, as directed by the physician.

A patient or caregiver should use the smallest amount of Elidel Cream needed to

control the signs and symptoms of eczema.

Caregivers applying Elidel Cream to a patient, or a patient who is not treating the

hands should wash their hands with soap and water after applying Elidel Cream. This

should remove any cream left on the hands.

A patient should not bathe, shower or swim right after applying Elidel Cream. This

could wash off the cream.

A patient can use moisturizers with Elidel Cream. They should be sure to check with

the physician first about the products that are right for them. Because the skin of

patients with eczema can be very dry, it is important they keep up good skin care

practices. If a patient uses moisturizers, he or she should apply them after Elidel

Cream.

What should a patient avoid while using Elidel Cream?

A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet

light therapy during treatment with Elidel Cream.

A patient should limit sun exposure during treatment with Elidel Cream even when

the medicine is not on the skin. If a patient needs to be outdoors after applying Elidel

Cream, the patient should wear loose fitting clothing that protects the treated area

from the sun. The physician should advise the patient about other types of protection

from the sun.

A patient should not cover the skin being treated with bandages, dressings or wraps.

A patient can wear normal clothing.

Care should be taken to avoid contact with eyes and mucous membranes. If

accidentally applied to these areas, the cream should be thoroughly wiped off and

rinsed off with water.

A patient should not swallow Elidel Cream and should contact the physician if they

Drug Interactions

Potential interactions between Elidel and other drugs, including immunizations, have

not been systematically evaluated. Due to low blood levels of pimecrolimus detected

in some patients after topical application, systemic drug interactions are not expected,

but cannot be ruled out. The concomitant administration of known CYP3A family of

inhibitors in patients with widespread and/or erythrodermic disease should be done

with caution. Some examples of such drugs are erythromycin, itraconazole,

ketoconazole, fluconazole, calcium channel blockers and cimetidine.

A study that included 79 infants treated for up to 2 years showed that treatment with

Elidel 1% Cream did not interfere with the protective immune response to childhood

vaccinations. Application of Elidel 1% cream to vaccination sites, as long as local

reactions persist, was not studied and is therefore not recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year rat dermal carcinogenicity study using Elidel Cream, a statistically

significant increase in the incidence of follicular cell adenoma of the thyroid was

noted in low, mid and high dose male animals compared to vehicle and saline control

male animals. Follicular cell adenoma of the thyroid was noted in the dermal rat

carcinogenicity study at the lowest dose of 2 mg/kg/day [0.2% pimecrolimus cream;

1.5X the Maximum Recommended Human Dose (MRHD) based on AUC

comparisons]. No increase in the incidence of follicular cell adenoma of the thyroid

was noted in the oral carcinogenicity study in male rats up to 10 mg/kg/day

(66X MRHD based on AUC comparisons). However, oral studies may not reflect

continuous exposure or the same metabolic profile as by the dermal route. In a mouse

dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase

in incidence of neoplasms was observed in the skin or other organs up to the highest

dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27X MRHD based on AUC

comparisons. However, lymphoproliferative changes (including lymphoma) were

noted in a 13 week repeat dose dermal toxicity study conducted in mice using

pimecrolimus in an ethanolic solution at a dose of 25 mg/kg/day (47X MRHD based

on AUC comparisons). No lymphoproliferative changes were noted in this study at a

dose of 10 mg/kg/day (17X MRHD based on AUC comparison). However, the

latency time to lymphoma formation was shortened to 8 weeks after dermal

administration of pimecrolimus dissolved in ethanol at a dose of 100 mg/kg/day (179-

217X MRHD based on AUC comparisons).

In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in

the incidence of lymphoma was noted in high dose male and female animals

compared to vehicle control male and female animals. Lymphomas were noted in the

oral mouse carcinogenicity study at a dose of 45 mg/kg/day (258-340X MRHD based

on AUC comparisons). No drug-related tumors were noted in the mouse oral

carcinogenicity study at a dose of 15 mg/kg/day (60-133X MRHD based on AUC

comparisons). In an oral (gavage) rat carcinogenicity study, a statistically significant

increase in the incidence of benign thymoma was noted in 10 mg/kg/day

pimecrolimus treated male and female animals compared to vehicle control treated

male and female animals. In addition, a significant increase in the incidence of benign

thymoma was noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day

pimecrolimus treated male animals compared to vehicle control treated male animals.

No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1

mg/kg/day male animals (1.1X MRHD based on AUC comparisons) and at a dose of

5 mg/kg/day for female animals (21X MRHD based on AUC comparisons).

In a 52-week dermal photo-carcinogenicity 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 (40 weeks of treatment followed by 12 weeks of

observation) with the Elidel Cream vehicle alone. No additional effect on tumor

development beyond the vehicle effect was noted with the addition of the active

ingredient, pimecrolimus, to the vehicle cream.

A 39-week oral monkey toxicology study was conducted with pimecrolimus doses of

15, 45 and 120 mg/kg/day. A dose dependent increase in expression of

immunosuppressive-related lymphoproliferative disorder (IRLD) associated with

lymphocryptovirus (a monkey strain of virus related to human Epstein Barr virus) was

observed. IRLD in monkeys mirrors what has been noted in human transplant patients

after chronic systemic immunosuppressive therapy, post transplantation

lymphoproliferative disease (PTLD), after treatment with chronic systemic

immunosuppressive therapy. Both IRLD and PTLD can progress to lymphoma, which

is dependent on the dose and duration of systemic immunosuppressive therapy. A

dose dependent increase in opportunistic infections (a signal of systemic

immunosuppression) was also noted in this monkey study. A no observed adverse

effect level (NOAEL) for IRLD and opportunistic infections was not established in

this study. IRLD occurred at the lowest dose of 15 mg/kg/day for 39 weeks [31X the

Maximum Recommended Human Dose (MRHD) of Elidel Cream based on AUC

comparisons] in this study. A partial recovery from IRLD was noted upon cessation of

dosing in this study.

A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma

L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an

in vivo mouse micronucleus test revealed no evidence for a mutagenic or clastogenic

potential for the drug.

An oral fertility and embryofetal developmental study in rats revealed estrus cycle

disturbances, post-implantation loss and reduction in litter size at the 45 mg/kg/day

dose (38X MRHD based on AUC comparisons). No effect on fertility in female rats

was noted at 10 mg/kg/day (12X MRHD based on AUC comparisons). No effect on

fertility in male rats was noted at 45 mg/kg/day (23X MRHD based on AUC

comparisons), which was the highest dose tested in this study.

A second oral fertility and embryofetal developmental study in rats revealed reduced

testicular and epididymal weights, reduced testicular sperm counts and motile sperm

for males and estrus cycle disturbances, decreased corpora lutea, decreased

implantations and viable fetuses for females at 45 mg/kg/day dose (123X MRHD for

males and 192X MRHD for females based on AUC comparisons). No effect on

fertility in female rats was noted at 10 mg/kg/day (5X MRHD based on AUC

comparisons). No effect on fertility in male rats was noted at 2 mg/kg/day (0.7X

MRHD based on AUC comparisons).

Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies of topically administered

pimecrolimus in pregnant women. The experience with Elidel Cream when used by

pregnant women is too limited to permit assessment of the safety of its use during

pregnancy.

In dermal embryofetal developmental studies, no maternal or fetal toxicity was

observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus

cream) in rats (0.14X MRHD based on body surface area) and 10 mg/kg/day (1%

pimecrolimus cream) in rabbits (0.65X MRHD based on AUC comparisons). The 1%

pimecrolimus cream was administered topically for 6 hours/day during the period of

organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-

20 in rabbits).

A second dermal embryofetal development study was conducted in rats using

pimecrolimus cream applied dermally to pregnant rats (1g cream/kg body weight of

0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2,

6, and 10 mg/kg/day with daily exposure of approximately 22 hours. No maternal,

reproductive, or embryo-fetal toxicity attributable to pimecrolimus was noted at 10

mg/kg/day (0.66X MRHD based on AUC comparisons), the highest dose evaluated in

this study. No teratogenicity was noted in this study at any dose.

A combined oral fertility and embryofetal developmental study was conducted in rats

and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus

was administered during the period of organogenesis (2 weeks prior to mating until

gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45

mg/kg/day in rats and 20 mg/kg/day in rabbits. In the absence of maternal toxicity,

indicators of embryofetal toxicity (post-implantation loss and reduction in litter size)

were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in the oral

fertility and embryofetal developmental study conducted in rats. No malformations in

the fetuses were noted at 45 mg/kg/day (38X MRHD based on AUC comparisons) in

this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the

oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9X MRHD

based on AUC comparisons), which was the highest dose tested in this study.

A second oral embryofetal development study was conducted in rats. Pimecrolimus

was administered during the period of organogenesis (gestational days 6 – 17) at

doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity

were noted at 45 mg/kg/day (271X MRHD based on AUC comparisons). A slight

increase in skeletal variations that were indicative of delayed skeletal ossification was

also noted at this dose. No maternal toxicity, embryolethality or fetotoxicity were

noted at 10 mg/kg/day (16X MRHD based on AUC comparisons). No teratogenicity

was noted in this study at any dose.

A second oral embryofetal development study was conducted in rabbits.

Pimecrolimus was administered during the period of organogenesis (gestational days

7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and

fetotoxicity were noted at 20 mg/kg/day (12X MRHD based on AUC comparisons). A

slight increase in skeletal variations that were indicative of delayed skeletal

ossification was also noted at this dose. No maternal toxicity, embryotoxicity or

fetotoxicity were noted at 6 mg/kg/day (5X MRHD based on AUC comparisons). No

teratogenicity was noted in this study at any dose.

An oral peri- and post-natal developmental study was conducted in rats. Pimecrolimus

was administered from gestational day 6 through lactational day 21 up to a dose level

of 40 mg/kg/day. Only 2 of 22 females delivered live pups at the highest dose of 40

mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent

maturation and fertility were not affected at 10 mg/kg/day (12X MRHD based on

AUC comparisons), the highest dose evaluated in this study.

Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal

developmental studies.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response,

this drug should be used only if clearly needed during pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential

for serious adverse reactions in nursing infants from pimecrolimus, a decision should

be made whether to discontinue nursing or to discontinue the drug, taking into

account the importance of the drug to the mother.

Pediatric Use

For infants (3 to 23 months), children (2to 11 years), and adolescents (12to 17 years)

the dosing recommendation is the same as for adults.

Use in babies under 3 months of age has not been evaluated.

The long term safety and effects of Elidel Cream on the developing immune system

are unknown. (see

WARNINGS,

INDICATIONS AND USAGE

Three Phase 3 pediatric studies were conducted involving 1,114 patients 2-17 years of

age. Two studies were 6-week randomized vehicle-controlled studies with a 20-week

open-label phase and one was a vehicle-controlled (up to 1 year) safety study with the

option for sequential topical corticosteroid use. Of these patients 542 (49%) were 2-6

years of age. In the short-term studies, 11% of Elidel patients did not complete these

studies and 1.5% of Elidel patients discontinued due to adverse events. In the one-

year study, 32% of Elidel patients did not complete this study and 3% of Elidel

patients discontinued due to adverse events. Most discontinuations were due to

unsatisfactory therapeutic effect.

The most common local adverse event in the short-term studies of Elidel Cream in

pediatric patients ages 2-17 was application site burning (10% vs. 13% vehicle); the

incidence in the long-term study was 9% Elidel vs. 7% vehicle (see

ADVERSE

REACTIONS

). Adverse events that were more frequent (>5%) in patients treated

with Elidel Cream compared to vehicle were headache (14% vs. 9%) in the short-term

trial. Nasopharyngitis (26% vs. 21%), influenza (13% vs. 4%), pharyngitis (8% vs.

3%), viral infection (7% vs. 1%), pyrexia (13% vs. 5%), cough (16% vs. 11%), and

headache (25% vs. 16%) were increased over vehicle in the 1-year safety study (see

ADVERSE REACTIONS

). In 843 patients ages 2-17 years treated with Elidel

Cream, 9 (0.8%) developed eczema herpeticum (5 on Elidel Cream alone and 4 on

Elidel Cream used in sequence with corticosteroids). In 211 patients on vehicle alone,

there were no cases of eczema herpeticum. The majority of adverse events were mild

to moderate in severity.

Two Phase 3 studies were conducted involving 436 infants age 3 months - 23 months.

One 6- week randomized vehicle-controlled study with a 20-week open-label phase

and one safety study, up to one year, were conducted. In the 6-week study, 11% of

Elidel and 48% of vehicle patients did not complete this study; no patient in either

group discontinued due to adverse events. Infants on Elidel Cream had an increased

incidence of some adverse events compared to vehicle. In the 6-week vehicle-

controlled study these adverse events included pyrexia (32% vs. 13% vehicle), URI

(24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis

media (4% vs. 0%), and diarrhea (8% vs. 0%). In the open-label phase of the study,

for infants who switched to Elidel Cream from vehicle, the incidence of the above-

cited adverse events approached or equaled the incidence of those patients who

remained on Elidel Cream. In the 6 month safety data, 16% of Elidel and 35% of

vehicle patients discontinued early and 1.5% of Elidel and 0% of vehicle patients

discontinued due to adverse events. Infants on Elidel Cream had a greater incidence of

some adverse events as compared to vehicle. These included pyrexia (30% vs. 20%),

URI (21% vs. 17%), cough (15% vs. 9%), hypersensitivity (8% vs. 2%), teething

(27% vs. 22%), vomiting (9% vs. 4%), rhinitis (13% vs. 9%), viral rash (4% vs. 0%),

rhinorrhea (4% vs. 0%), and wheezing (4% vs. 0%).

Geriatric Use

Nine (9) patients ≥ 65 years old received Elidel Cream in Phase 3 studies. Clinical

studies of Elidel did not include sufficient numbers of patients aged 65 and over to

assess efficacy and safety.

ADVERSE REACTIONS

No phototoxicity and no photoallergenicity were detected in clinical studies with 24

and 33 normal volunteers, respectively. In human dermal safety studies, Elidel

(pimecrolimus) Cream 1% did not induce contact sensitization, or cumulative

irritation.

In a one-year safety study in pediatric patients age 2-17 years old involving sequential

use of Elidel Cream and a topical corticosteroid, 43% of Elidel patients and 68% of

vehicle patients used corticosteroids during the study. Corticosteroids were used for

more than 7 days by 34% of Elidel patients and 54% of vehicle patients. An increased

incidence of impetigo, skin infection, superinfection (infected atopic dermatitis),

rhinitis, and urticaria were found in the patients that had used Elidel Cream and

topical corticosteroid sequentially as compared to Elidel Cream alone.

In 3 randomized, double-blind vehicle-controlled pediatric studies and one active-

controlled adult study, 843 and 328 patients respectively, were treated with Elidel

Cream. In these clinical trials, 48 (4%) of the 1171 Elidel patients and 13 (3%) of 408

vehicle-treated patients discontinued therapy due to adverse events. Discontinuations

for AEs were primarily due to application site reactions, and cutaneous infections.

The most common application site reaction was application site burning, which

occurred in 8%-26% of patients treated with Elidel Cream.

The following table depicts the incidence of adverse events pooled across the 2

identically designed 6 week studies with their open label extensions and the 1-year

safety study for pediatric patients ages 2-17. Data from the adult active-controlled

study is also included in this table. Adverse events are listed regardless of relationship

to study drug.

Treatment Emergent Adverse Events (≥1%) in Elidel Treatment Groups

Two cases of septic arthritis have been reported in infants less than one year of age in

clinical trials conducted with Elidel Cream (n = 2443). Causality has not been

established.

POST-MARKETING EVENTS

The following adverse reactions have been reported in patients using Elidel Cream.

Because these reactions are reported voluntarily from a population of uncertain size, it

is not always possible to reliably estimate their frequency or establish a causal

relationship to drug exposure.

General:

Anaphylactic reactions, ocular irritation after application of the cream to the

eye lids or near the eyes, angioneurotic edema, facial edema, skin flushing associated

with alcohol use.

Hematology/Oncology:

Lymphomas, basal cell carcinoma, malignant melanoma,

squamous cell carcinoma

OVERDOSAGE

There has been no experience of overdose with Elidel

(pimecrolimus) Cream 1%. If

oral ingestion occurs, medical advice should be sought.

DOSAGE AND ADMINISTRATION

The patient or care giver should apply a thin layer of Elidel

(pimecrolimus) Cream

1% to the affected skin twice daily. The patient or caregiver should stop using when

signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on

what actions to take if symptoms recur.

If signs and symptoms persist and beyond 6 weeks, patients should be re-examined

by their health care provider to confirm the diagnosis of atopic dermatitis.

Continuous long-term use of Elidel Cream should be avoided, and application

should be limited to areas of involvement with atopic dermatitis.

The safety of Elidel Cream under occlusion, which may promote systemic exposure,

has not been evaluated. Elidel Cream should not be used with occlusive dressings.

HOW SUPPLIED

Elidel (pimecrolimus) Cream 1% is available in tubes of 15 and 30 grams.

Store at 25°C. Do not freeze.

Once opened, the contents of the tube should be used within 1 year.

Manufacturer:

Novartis Pharma Produktions GmbH, Germany

for MEDA Pharma GmbH & Co. KG, Germany.

Licence Holder:

Megapharm Ltd.,

P.O.B. 519,

Hod-Hasharon 45105.