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Safety and Tolerability of Pimecrolimus Cream 1% in Infants: Experience in 1133 Patients Treated for up to 2 Years << back to index

 

In the clinical development program of pimecrolimus cream 1% for atopic dermatitis (AD), a total of 1133 infants (aged 3-23 months) with mild to severe AD were treated intermittently with pimecrolimus cream 1% for up to 2 years.

This document summarizes the safety and tolerability of pimecrolimus cream 1% in infants with AD on the basis of the combined data from 4 pharmacokinetic studies and 6 clinical trials conducted in 1133 patients. Publication of this safety assessment is pending.

Systemic exposure in pharmacokinetic studies

Four pharmacokinetic studies conducted included 35 infants aged from 3.4 to 22.7 months with moderate to severe AD involving from 10% to 92% of the total body surface area (TBSA) at baseline (Harper et al, 2001, Allen et al, 2003 and Lakhanpaul et al, 2002). Thirty infants were treated for 3 weeks and 5 continued treatment for up to 1 year.

Overall, the results of pharmacokinetic studies in infants indicate that treatment with pimecrolimus cream 1% leads to minimal systemic exposure, even in patients with extensive disease, and that pimecrolimus blood concentrations remain low during treatment for up to 1 year. Pimecrolimus blood concentrations were consistently low (= 1 ng/mL) in more than 80% of samples. The highest concentration measured (2.6 ng/mL) was well below the mean peak concentration (54 ng/mL) detected in adult psoriasis patients treated orally for 28 days with 30 mg pimecrolimus twice daily, a dose which was well tolerated. In line with these findings, no clinically relevant systemic adverse events were reported in the infants enrolled in the pharmacokinetic studies.

Clinical studies

Six double-blind (DB) or open-label (OL) studies evaluated the efficacy, safety and tolerability of pimecrolimus cream 1% in infants with AD for periods ranging from 4 weeks to 2 years (Ho et al, 2003, Kapp et al 2002, Papp et al, 2005 and Papp at al, 2005). Four of the six studies were either DB trials or trials involving a DB phase during which patients were treated intermittently with pimecrolimus cream 1% or vehicle for periods ranging from 4 weeks to 12 months. In total, 1098 patients aged 3 to 23 months (530 aged < 12 months) were included in the six studies: 637 (58.0%) were treated for at least 5 months, 466 (42.4%) for at least 6 months, 237 (21.6%) for at least 11 months, 190 (17.3%) for at least 1 year, 68 (6.2%) for at least 23 months and 61 (5.6%) for at least 2 years.

Combined Analysis of the Incidence of Adverse Events

In the 4 vehicle-controlled, DB studies, the discontinuation rates ranged from 9.4% to 25% in the pimecrolimus groups and from 29% to 48% in the vehicle groups. The main reason for this imbalance was the higher incidence of premature discontinuations due to unsatisfactory therapeutic effect in the vehicle groups (range: 14% to 41%) in comparison with the pimecrolimus groups (range: 0 to 10%). To account for the time on studies and multiplicity of adverse events of the same type, the total number of event occurrences (i.e., events count) during the studies were analyzed using the incidence density (ID) rate of all adverse events.
Data from all infant studies were pooled for this analysis to provide the largest available infant dataset of adverse events.

Most Frequently Reported Adverse Events

The incidence density (ID) rates for adverse events that occurred in more than 1% of patients in any group are presented in Table 1. The majority of the most frequently reported adverse events were common childhood disorders such as nasopharyngitis, pyrexia, upper respiratory tract infection, ear infection and bronchitis. The ID rate for all adverse events was similar in the Pimecrolimus DB and Vehicle DB groups, except for teething (discomfort experienced during the eruption of teeth through the gums), which was observed more frequently in patients treated with pimecrolimus cream 1% than in patients treated with the vehicle (relative risk: 2.02; 95% CI: 1.32-3.27; P = 0.002).

 

Effects on the Immune System

The incidence of systemic infections and skin infections was analyzed to detect any possible sign of immunosuppression associated with the use of pimecrolimus cream 1%. The analysis of adverse events described above showed no statistically significant difference in the ID rates for the most frequently reported systemic infections between the Pimecrolimus DB group and the Vehicle DB group (Table 1). The ID rates for total bacterial, fungal, parasitic and viral skin infections were also comparable in the Pimecrolimus DB and Vehicle DB groups Table 2.

In total, 10 infants in the 6 clinical studies experienced clinically diagnosed eczema herpeticum (it is a form of herpes simplex virus infection with extensive skin involvement occurring predominantly in patients with AD). In none of the patients was the diagnosis confirmed by virological culture, polymerase chain reaction for viral DNA, or immunofluorescence analysis using virus-specific antibodies. All the patients affected were using pimecrolimus cream 1%. The ID rate for eczema herpeticum for infants in the Total Pimecrolimus group was 1.3 per 1000 patient-months of observation, which appeared to be similar to the ID rate of eczema herpeticum of 1.37 per 1000 patient-months of observation calculated for children older than 2 years treated with pimecrolimus cream 1%.

To evaluate further the systemic immunosuppressive potential of pimecrolimus cream 1%, its effect on the immune response to vaccinations was assessed in 91 infants and young children who completed the 1-year DB study 0315 and were subsequently followed for a further year (study 0315-E1) (Papp et al, 2005 and Papp et al, 2005). Seventy-six of these 91 patients had received pimecrolimus cream 1% and 15 had received control treatment (vehicle plus use of moderately potent TCSs in case of severe flares) in the first year. During the second year, all patients were treated with pimecrolimus cream 1% at the first sign or symptom of AD and as long as signs or symptoms of the disease persisted. Serum concentrations of antibodies against tetanus, diphtheria, measles and rubella were measured at Months 18 and 24. Analysis of the serum concentrations of specific antibodies revealed seropositivity rates of 94% for tetanus, 89% for diphtheria, 89% for measles and 84% for rubella, which were comparable to those reported in literature.

 

Conclusions

Pimecrolimus blood concentrations following topical applications were consistently low, irrespective of the level of disease severity and percentage of total body surface area involved. The level of systemic exposure to pimecrolimus in infants was comparable to that observed in older pediatric patients enrolled in the same studies and treated in the same way with pimecrolimus cream 1%, suggesting that young pediatric patients are not at higher risk of significant percutaneous absorption of topically applied pimecrolimus despite their large skin surface area to body mass ratio.

During the DB studies and DB phases, the incidence of the majority of the most frequently reported adverse events was similar in patients who received pimecrolimus cream 1% and in patients who received the vehicle. The occurrence of adverse events did not increase over time in patients treated with pimecrolimus cream 1% for up to 2 years. There was no demonstrable sign of systemic immunosuppression as pimecrolimus cream 1% did not increase the overall incidence of systemic infections, compared with the vehicle, and its use did not affect the ability to mount a normal immune response to vaccinations.

In general, treatment with pimecrolimus cream 1% did not appear to be associated with an increased incidence of total skin infections. During the DB studies and DB phases, the incidence of the most frequently reported skin infections and herpes virus infections was similar in infants who received pimecrolimus cream % and in those who received the vehicle. Nonetheless, all cases of clinically diagnosed eczema herpeticum reported in the studies considered here occurred in patients on treatment with pimecrolimus cream 1%. In case of suspicion of eczema herpeticum in AD patients treated with pimecrolimus cream 1%, treatment should be stopped at the site of infection and appropriate antiviral therapy should be initiated. After recovery, treatment with pimecrolimus cream 1% can be resumed.

We believe this review of data from a large number of patients provides useful information on the type of side effects infants can experience during treatment with pimecrolimus cream 1% for AD, and on the risk of developing those side effects. Because of the low level of systemic absorption and good tolerability during intermittent use in the long term, pimecrolimus cream 1% may represent an alternative to TCSs in young pediatric patients, as they constitute at the same time the segment of the population most frequently affected by AD and the segment of the affected population most susceptible to the systemic effects of prolonged TCS treatment.

 

References

Allen BR, Lakhanpaul M, Morris A, et al. Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients. Arch Dis Child. 2003; 88: 969- 973.

Harper J, Green A, Scott G, et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol. 2001; 144: 781-787.

Ho VC, Gupta A, Kaufmann R, et al. Safety and efficacy of nonsteroid pimecrolimus cream
1% in the treatment of atopic dermatitis in infants. J Pediatr. 2003; 142: 155-162.

Kapp A, Papp K, Bingham A, et al. Flare Reduction in Eczema with Elidel (infants) multicentre investigator study group: Long-term management of atopic dermatitis in Summary of Safety in Infants—combined analysis infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol. 2002; 110: 277-284.

Lakhanpaul M, Davies T, Allen B, Stephenson T, Scott G, Ebelin ME. Pimecrolimus (SDZ ASM 981) cream 1%: minimal systemic absorption in infants with atopic dermatitis during long-term treatment [abstract]. Ann Dermatol Venereol. 2002; 129 (Suppl 1): 415.

Papp KA, Werfel T, Fölster-Holst R, et al. Long-term control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a two-year study. J Am Acad Dermatol. 2005; 52: 240-246.

Papp KA, Breuer K, Meurer M, et al. Long-term treatment of atopic dermatitis with pimecrolimus cream 1% in infants does not interfere with the development of protective antibodies after vaccination. J Am Acad Dermatol. 2005; 52: 247-253.

Table 1:  Incidence density per 1000 Patient-months of Follow-up for the Most Frequently Observed Adverse Events (>1% of Patients in any Group), With Relative Risk, 95% Cl and P-values


Adverse Events ID
Pimecrolimus
DB*
ID Vehicle
DB
Relative
risk
95% Cl P-value ID Total
Pimecrolimus

Total 961 906 1.061 0.97-1.17 0.216 741
Asthma 10.5 5.0 2.078 0.73-8.70 0.229 8.1
Bronchitis 28.7 33.6 0.854 0.53-1.44 0.532 26.3
Chickenpox/
Varicella
10.8 8.4 1.293 0.54-3.81 0.596 7.5
Conjunctivitis 15.1 16.8 0.901 0.47-1.91 0.768 12
Contact
dermatitis
14.7 13.4 1.097 0.54-2.53 0.812 8.7
Cough 43 38.6 1.114 0.73-1.79 0.636 41.4
Diarrhea 32.9 28.5 1.115 0.70-2.01 0.588 26.4
Ear Infection 30.2 23.5 1.287 0.75-2.37 0.385 18.9
Gastroenteritis 14.7 16.8 0.877 0.46-1.86 0.713 11.7
Hypersensitivity 12.8 6.7 1.905 0.76-6.39 0.223 5.6
Impetigo 10.8 13.4 0.808 0.39-1.90 0.595 7.2
Influenza 8.1 11.7 0.693 0.31-1.76 0.400 7.3
Nasopharyngitis 128 114 1.121 0.87-1.47 0.392 105
Otitis Media 21.7 20.1 1.078 0.60-2.11 0.814 20.7
Pyrexia 82.5 70.5 1.171 0.85-1.65 0.350 70.1
Rhinitis 48.8 41.9 1.164 0.77-1.83 0.488 27.3
Teething 71.3 35.2 2.023 1.32-3.27 0.002 35.5
Tonsillitis 10.5 8.4 1.247 0.52-3.68 0.650 8.2
Upper respiratory tract infection 60.1 65.4 0.918 0.65-1.32 0.632 47.9
Urticaria 8.9 10.1 0.885 0.38-2.40 0.790 5.1
Vomiting 19.0 18.5 1.029 0.56-2.08 0.933 13.9

*N = 495, month follow-up = 2581
†N = 193, month follow-up = 596
‡N = 1098, months follow-up = 7686, Total Pimecrolimus = all patients treated with pimecrolimus cream 1%: data from DB phases were pooled with data from OL phases or studies.

Tabel 2:  Incidence Density per 1000 Patient-months of Follow-up for Skin Infections with ID rates =2 per 1000 Patient-months in Any Group, With Relative Risk, 95% Cl and P-values

Skin infections ID
Pimecrolimus
DB*
ID Vehicle
DB
Relative
risk
95% Cl P-value ID Total
Pimecrolimus
Overall Bacterial 71.3 63.8 1.118 0.80-1.61 0.531 46.6
Total 25.6 25.2 1.016 0.60-1.85 0.956 15.6
Bacterial infection 6.2 6.7 0.924 0.34-3.22 0.887 3.3
Impetigo 10.8 13.4 0.808 0.39-1.90 0.595 7.2
Stye 3.1 0 1.0
Fungal
Total 14.3 6.7 2.136 0.86-7.13 0.149 8.1
Candida 3.1 0 2.1
Oral candidiasis 5.4 3.4 1.616 0.45-10.3 0.525 3.0
Skin fungal infection 3.5 3.4 1.039 0.27-6.82 0.961 2.1
Parasitic
Total 1.9 3.4 0.577 0.12-4.03 0.511 0.8
Scabies infestation 1.9 3.4 0.577 0.12-4.03 0.511 0.8
Viral
Total 19.0 11.7 1.616 0.78-3.91 0.235 15.0
Chickenpox/
Varicella
10.8 8.4 1.293 0.54-3.81 0.596 7.5
Molluscum contagiosum 1.5 0 2.2
Viral rash 4.3 1.7 2.540 0.49-46.4 0.372 2.2
Non Specified
Total 10.5 16.8 0.623 0.31-1.35 0.202 7.2
Skin infection 5.8 11.7 0.495 0.21-1.30 0.124 2.9
Superinfection 2.7 3.4 0.808 0.20-5.42 0.791 2.7