Topical Immunosuppressants

Pediatric Subcommittee of the AIDACPediatric Subcommittee of the AIDACOctober 29-30, 2003October 29-30, 2003

Topical ImmunosuppressantsTopical ImmunosuppressantsTopical ImmunosuppressantsTopical Immunosuppressants

Bindi M. Nikhar, M.D., FAAPDivision of Dermatologic and Dental Drug Products, ODE V

Bindi M. Nikhar, M.D., FAAPDivision of Dermatologic and Dental Drug Products, ODE V

2Pediatric Subcommittee of the AIDACPediatric Subcommittee of the AIDACOctober 29-30, 2003October 29-30, 2003

TOPICAL TOPICAL IMMUNOSUPPRESSANTSIMMUNOSUPPRESSANTS

TOPICAL TOPICAL IMMUNOSUPPRESSANTSIMMUNOSUPPRESSANTS

• Newest pharmacological class for AD • Introduced in this decade • Direct immunosuppressive action in

diseases with an immunological basis• 2 currently FDA approved products• Tacrolimus (FK506) (trade name Protopic)• Pimecrolimus (SDZ ASM 981) (trade name

Elidel)

• Newest pharmacological class for AD • Introduced in this decade • Direct immunosuppressive action in

diseases with an immunological basis• 2 currently FDA approved products• Tacrolimus (FK506) (trade name Protopic)• Pimecrolimus (SDZ ASM 981) (trade name

Elidel)


BackgroundBackgroundBackgroundBackground

• Tacrolimus ointment approved on 12/08/2000, 0.03% ointment approved for children 2 to 15 years, 0.1% ointment approved for adults.

• Indication in both age groups is short and intermittent long term therapy of patients with moderate to severe AD.

• Systemic Tacrolimus (Prograf) first introduced for prevention of allograft rejection, now used in kidney, liver and heart transplantation

• Tacrolimus ointment approved on 12/08/2000, 0.03% ointment approved for children 2 to 15 years, 0.1% ointment approved for adults.

• Indication in both age groups is short and intermittent long term therapy of patients with moderate to severe AD.

• Systemic Tacrolimus (Prograf) first introduced for prevention of allograft rejection, now used in kidney, liver and heart transplantation


• Elidel cream 1% approved on 12/13/2001.• Indicated for patients 2 years of age and older for

short and intermittent long term therapy in the treatment of mild to moderate atopic dermatitis.

• Both drugs not approved for use in children less than 2 years of age.

• Systemic absorption can take place in both adult and pediatric age groups from the topical application of both drugs.

• Currently, the effects of topical immunosuppressants on the developing immune system are unknown.

• Elidel cream 1% approved on 12/13/2001.• Indicated for patients 2 years of age and older for

short and intermittent long term therapy in the treatment of mild to moderate atopic dermatitis.

• Both drugs not approved for use in children less than 2 years of age.

• Systemic absorption can take place in both adult and pediatric age groups from the topical application of both drugs.

• Currently, the effects of topical immunosuppressants on the developing immune system are unknown.

Background (cont’d)Background (cont’d)Background (cont’d)Background (cont’d)


Pharmacokinetic (PK) studies for Pharmacokinetic (PK) studies for TacrolimusTacrolimus

Pharmacokinetic (PK) studies for Pharmacokinetic (PK) studies for TacrolimusTacrolimus

• Pooled results from 2 PK studies in 49 adult moderate-severe AD patients indicate that tacrolimus is absorbed after the topical application of 0.1% Protopic ointment.

• Peak tacrolimus levels ranged from undetectable to 20 ng/ml after single or multiple doses of 0.1% Protopic ointment, 45 out of the 49 patients had peak concentrations less than 5 ng/ml.

• Pooled results from 2 PK studies in 49 adult moderate-severe AD patients indicate that tacrolimus is absorbed after the topical application of 0.1% Protopic ointment.

• Peak tacrolimus levels ranged from undetectable to 20 ng/ml after single or multiple doses of 0.1% Protopic ointment, 45 out of the 49 patients had peak concentrations less than 5 ng/ml.


Pharmacokinetic studies for Pharmacokinetic studies for Tacrolimus (cont’d)Tacrolimus (cont’d)

Pharmacokinetic studies for Pharmacokinetic studies for Tacrolimus (cont’d)Tacrolimus (cont’d)

• A PK study of 0.1% Protopic ointment in 20 pediatric AD patients (ages 6-13 years), showed peak tacrolimus concentrations below 1.6 ng/ml in all patients.

• Absolute bioavailability of topical tacrolimus is unknown.

• Using iv historical data for comparison, the bioavailability of tacrolimus from Protopic in AD patients is < 0.5%.

• Lowest tacrolimus blood level at which systemic effects can be observed is not known.

• A PK study of 0.1% Protopic ointment in 20 pediatric AD patients (ages 6-13 years), showed peak tacrolimus concentrations below 1.6 ng/ml in all patients.

• Absolute bioavailability of topical tacrolimus is unknown.

• Using iv historical data for comparison, the bioavailability of tacrolimus from Protopic in AD patients is < 0.5%.

• Lowest tacrolimus blood level at which systemic effects can be observed is not known.


Pharmacokinetic studies for Pharmacokinetic studies for PimecrolimusPimecrolimus

Pharmacokinetic studies for Pharmacokinetic studies for PimecrolimusPimecrolimus

• In adults treated for AD with 13–62% BSA involvement for periods up to a year, detectable pimecrolimus blood concentrations were < 2 ng/ml (LOQ <0.5 ng/ml).

• In 26 pediatric patients between 2-14 years with AD (20-69% BSA involvement) who had b.i.d. application for 3 weeks, blood concentrations of pimecrolimus were < 3 ng/ml (LOQ < 0.5 ng/ml)

• In adults treated for AD with 13–62% BSA involvement for periods up to a year, detectable pimecrolimus blood concentrations were < 2 ng/ml (LOQ <0.5 ng/ml).

• In 26 pediatric patients between 2-14 years with AD (20-69% BSA involvement) who had b.i.d. application for 3 weeks, blood concentrations of pimecrolimus were < 3 ng/ml (LOQ < 0.5 ng/ml)


Pharmacokinetic studies for Pharmacokinetic studies for Pimecrolimus (cont’d)Pimecrolimus (cont’d)


• 20 out of 23 children investigated had at least one detectable blood level as compared to adults (13 out of 25 investigated) over a 3 week period.

• In 22 pediatric patients aged 3 to 23 months with 10-92% BSA involvement, a higher proportion of blood levels ranging from 0.1 to 2.6 ng/ml (LOQ 0.1 ng/ml) was seen.

• 20 out of 23 children investigated had at least one detectable blood level as compared to adults (13 out of 25 investigated) over a 3 week period.

• In 22 pediatric patients aged 3 to 23 months with 10-92% BSA involvement, a higher proportion of blood levels ranging from 0.1 to 2.6 ng/ml (LOQ 0.1 ng/ml) was seen.




• This increase may be due to larger surface area to body mass ratio seen in younger subjects.

• A higher incidence of upper respiratory symptoms/infections was also seen in the 3-23 months age group relative to the older age group in PK studies.

• A causal relationship between these findings and Elidel use cannot be ruled out.

• This increase may be due to larger surface area to body mass ratio seen in younger subjects.

• A higher incidence of upper respiratory symptoms/infections was also seen in the 3-23 months age group relative to the older age group in PK studies.

• A causal relationship between these findings and Elidel use cannot be ruled out.


Pharmacokinetics (cont’d)Pharmacokinetics (cont’d)Pharmacokinetics (cont’d)Pharmacokinetics (cont’d)

Some factors leading to higher systemic levels include

• Higher body surface area• Younger age groups, especially the 3 to 23

month age groups as seen with pimecrolimus, this may be due to larger surface area to body mass ratio (this age group has not had pharmacokinetic testing for tacrolimus levels)

• Reduced skin barrier function eg. Netherton’s syndrome

Some factors leading to higher systemic levels include

• Higher body surface area• Younger age groups, especially the 3 to 23

month age groups as seen with pimecrolimus, this may be due to larger surface area to body mass ratio (this age group has not had pharmacokinetic testing for tacrolimus levels)

• Reduced skin barrier function eg. Netherton’s syndrome


Pediatric clinical studiesPediatric clinical studiesPediatric clinical studiesPediatric clinical studies

• Use of Protopic 0.03% ointment was studied in children 2-15 years of age by conducting 2 Phase 3 studies.

• In these studies, varicella zoster and vesiculobullous rash were seen more frequently in patients treated with Protopic ointment 0.03%, compared to vehicle.

• Use of Protopic 0.03% ointment was studied in children 2-15 years of age by conducting 2 Phase 3 studies.

• In these studies, varicella zoster and vesiculobullous rash were seen more frequently in patients treated with Protopic ointment 0.03%, compared to vehicle.


Pediatric clinical studies (cont’d)Pediatric clinical studies (cont’d)Pediatric clinical studies (cont’d)Pediatric clinical studies (cont’d)

• Elidel cream 0.1% was studied in infants 3-23 months of age and in children 2-17 years of age.

• In the 2-17 years age group, nasopharyngitis, influenza, viral infections, pyrexia ,cough, headache, eczema herpeticum were increased over vehicle in the 1 year safety study.

• Elidel cream 0.1% was studied in infants 3-23 months of age and in children 2-17 years of age.

• In the 2-17 years age group, nasopharyngitis, influenza, viral infections, pyrexia ,cough, headache, eczema herpeticum were increased over vehicle in the 1 year safety study.



• In the 3-23 months short term (6 week) infant study, pyrexia, URI, nasopharyngitis, gastroenteritis, otitis media, diarrhea seen more frequently compared to vehicle. The adverse event incidence for those in the open label phase of this study who switched over to Elidel cream from vehicle approached the incidence of those patients who remained on the cream.

• In the 3-23 months short term (6 week) infant study, pyrexia, URI, nasopharyngitis, gastroenteritis, otitis media, diarrhea seen more frequently compared to vehicle. The adverse event incidence for those in the open label phase of this study who switched over to Elidel cream from vehicle approached the incidence of those patients who remained on the cream.



• In the 6 month infant study safety data, adverse events occurring more frequently in the Elidel cream group compared to vehicle included pyrexia, URI, cough, vomiting, hypersensitivity, rhinitis, viral rash, rhinorrhea, and wheezing.

• In the 6 month infant study safety data, adverse events occurring more frequently in the Elidel cream group compared to vehicle included pyrexia, URI, cough, vomiting, hypersensitivity, rhinitis, viral rash, rhinorrhea, and wheezing.


Indications for use (Second-line)Indications for use (Second-line)Indications for use (Second-line)Indications for use (Second-line)

• Both Protopic and Elidel are indicated for patients in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or are intolerant of alternative, conventional therapies

• Both Protopic and Elidel are indicated for patients in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks, or in the treatment of patients who are not adequately responsive to or are intolerant of alternative, conventional therapies


Proposed Mechanisms of Proposed Mechanisms of ActionAction

Proposed Mechanisms of Proposed Mechanisms of ActionAction

* Both Tacrolimus and Pimecrolimus inhibit T-cell activation by binding to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12.

* The tacrolimus/pimecrolimus-FKBP complex further binds to calcineurin, which is an enzyme vital for early activation of both T helper cell types 1 and 2.

* Both Tacrolimus and Pimecrolimus inhibit T-cell activation by binding to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-12.

* The tacrolimus/pimecrolimus-FKBP complex further binds to calcineurin, which is an enzyme vital for early activation of both T helper cell types 1 and 2.


Adverse Effects of Topical Adverse Effects of Topical ImmunosuppressantsImmunosuppressants

Adverse Effects of Topical Adverse Effects of Topical ImmunosuppressantsImmunosuppressants

Local (Application site)• Burning• Pruritus• Erythema• Irritation • Edema• Urticaria

Local (Application site)• Burning• Pruritus• Erythema• Irritation • Edema• Urticaria


Adverse effects of Topical Adverse effects of Topical Immunosuppressants (cont’d)Immunosuppressants (cont’d)

Adverse effects of Topical Adverse effects of Topical Immunosuppressants (cont’d)Immunosuppressants (cont’d)

Systemic• Pyrexia• Upper and lower respiratory tract infection• Nasopharyngitis• Viral skin rashes eg. molluscum

contagiosum, herpes simplex, herpes zoster, eczema herpeticum

• Influenza

Systemic• Pyrexia• Upper and lower respiratory tract infection• Nasopharyngitis• Viral skin rashes eg. molluscum

contagiosum, herpes simplex, herpes zoster, eczema herpeticum

• Influenza


Adverse effects of Topical Adverse effects of Topical Immunosuppressants cont’dImmunosuppressants cont’dAdverse effects of Topical Adverse effects of Topical

Immunosuppressants cont’dImmunosuppressants cont’dSystemic side effects cont’d• Otitis media• Gastroenteritis, vomiting, diarrhea• Streptococcal pharyngitis, staphylococcal

infection• Skin infection NOS• Lymphadenopathy - In absence of a clear

etiology or in the presence of acute infectious mononucleosis, discontinuation recommended. Close monitoring required.

Systemic side effects cont’d• Otitis media• Gastroenteritis, vomiting, diarrhea• Streptococcal pharyngitis, staphylococcal

infection• Skin infection NOS• Lymphadenopathy - In absence of a clear

etiology or in the presence of acute infectious mononucleosis, discontinuation recommended. Close monitoring required.


Adverse effects of PrografAdverse effects of PrografAdverse effects of PrografAdverse effects of Prograf

• Patients receiving Prograf are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression. A lymphoproliferative disorder (LPD) related to Epstein-Barr virus infection has been reported in immunosuppressed patients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed.

• Patients receiving Prograf are at an increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression. A lymphoproliferative disorder (LPD) related to Epstein-Barr virus infection has been reported in immunosuppressed patients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed.


Potential long-term adverse Potential long-term adverse effects of topical effects of topical

immunosuppressantsimmunosuppressants

Potential long-term adverse Potential long-term adverse effects of topical effects of topical

immunosuppressantsimmunosuppressantsIncreased incidence of malignancies in

animal studies with topical tacrolimus(T) and pimecrolimus (P):–Lymphomas [P & T]–Follicular cell adenomas [P]–Skin tumors (with concurrent UV

radiation exposure) [P &T]

Increased incidence of malignancies in animal studies with topical tacrolimus(T) and pimecrolimus (P):–Lymphomas [P & T]–Follicular cell adenomas [P]–Skin tumors (with concurrent UV

radiation exposure) [P &T]


Since systemic use of calcineurin inhibitors is associated with formation of lymphomas and skin malignancies, low systemic exposure from topical calcineurin inhibitors over a course of time leading to a cumulative dose effect may lead to melanomas, non-melanoma skin cancers, Hodgkin’s and Non-Hodgkin’s lymphomas

Since systemic use of calcineurin inhibitors is associated with formation of lymphomas and skin malignancies, low systemic exposure from topical calcineurin inhibitors over a course of time leading to a cumulative dose effect may lead to melanomas, non-melanoma skin cancers, Hodgkin’s and Non-Hodgkin’s lymphomas

Potential long-term adverse Potential long-term adverse effects (cont’d)effects (cont’d)

Potential long-term adverse Potential long-term adverse effects (cont’d)effects (cont’d)


Concerns about long term side Concerns about long term side effectseffects

Concerns about long term side Concerns about long term side effectseffects

• Children from the age of 2 years and upwards (with off- label use expected in even younger children) will be using these medications on a short or intermittent long term basis

• About one third of children with moderate-severe AD may continue to use these drugs into teenage and adult years, thereby having a long duration of exposure.

• Children from the age of 2 years and upwards (with off- label use expected in even younger children) will be using these medications on a short or intermittent long term basis

• About one third of children with moderate-severe AD may continue to use these drugs into teenage and adult years, thereby having a long duration of exposure.


Concerns about long term side Concerns about long term side effects (cont’d)effects (cont’d)

Concerns about long term side Concerns about long term side effects (cont’d)effects (cont’d)

• Currently, we do not have long term safety data on either Tacrolimus or Pimecrolimus.

• Postmarketing evaluation of topical immunosuppressants is needed to evaluate this potential risk. Means of setting up these prospective studies need to be discussed.

• Currently, we do not have long term safety data on either Tacrolimus or Pimecrolimus.

• Postmarketing evaluation of topical immunosuppressants is needed to evaluate this potential risk. Means of setting up these prospective studies need to be discussed.

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Topical Immunosuppressants