804 Pharmacokinetics of the rivastigmine patch Table 1 Results from a randomised, double-blind, placebo-controlled trial of 1195 patients with mild-to-moderate AD: mean changes from baseline at week 24 for primary and secondary outcome measures, by double-blind treatment group (9.5 mg ⁄ 24 h rivastigmine patch, capsule and placebo groups), together with incidences of nausea and vomiting (19) Mean 24-week change from baseline 9.5 mg/24 h patch Capsule (3–12 mg/day) Placebo Primary outcomes ADAS-cog ADCS-CGIC Secondary outcomes MMSE ADCS-ADL Trail making test part A Adverse events, % Nausea Vomiting )0.6** 3.9** 1.1** )0.1** )12.3*** 7.2 6.2 )0.6** 3.9** 0.8** )0.5* )9.8*** 23.1*** 17.0*** 1.0 4.2 0.0 )2.3 7.7 5.0 3.3 ITT-LOCF population. MMSE, Mini-Mental State Examination; ADAS-cog, cognitive subscale of the Alzheimer’s Disease Assessment Scale; ADCS-ADL, Alzheimer’s Disease Cooperative Study Activities of Daily Living scale; ADCS-CGIC, Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change. Negative change scores on ADAS-cog and Trail Making Test part A indicate improvement. Negative change scores on MMSE and ADCS-ADL indicate deterioration. ADCS-CGIC is scored as a judgement of change, with 4.0 indicating no change, < 4.0 indicating improvement and > 4.0 indicating deterioration. *p £ 0.05, **p £ 0.01, ***p £ 0.001 vs. pla- cebo; p-values for ADAS-cog, ADCS-ADL and Trail Making Test part A are derived from two-way ANCOVA (explanatory variables: treat- ment, country and baseline scores), whereas p-values for ADCS-CGIC and MMSE are derived from the CMH van Elteren test using modiﬁed ridit scores with country as the stratiﬁcation variable. data have demonstrated a similar level of exposure to 6 mg ⁄ day capsules (64.1 vs. 60.0 ng h ⁄ ml respec- tively), which is considered an effective therapeutic dose (3–5). Also, fewer reports of nausea and vomit- ing were reported with the starting dose 4.6 mg ⁄ 24 h patch (1.9% and 0.5%, weeks 1–4), than the starting 3 mg ⁄ day capsule dose (3.1% and 2.0%; Novartis, data on ﬁle). Therefore, in contrast to the conven- tional capsule regimen (16-week, four-step titration from 3 to 12 mg ⁄ day), patients treated with the riv- astigmine patch are initiated on an effective dose with improved gastrointestinal tolerability, and can then be titrated in a single step to the recommended therapeutic dose (9.5 mg ⁄ 24 h patch) after only 4 weeks. The improved tolerability proﬁle of the patch also suggests that it may allow patients an easier path to higher doses, thereby enabling patients to stay on and beneﬁt from effective treatment for longer. This is reﬂected in the greater proportion of patients who achieved their target therapeutic dose in the 9.5 mg ⁄ 24 h patch group at the end of the study, compared with the 12 mg ⁄ day capsule group (95.9% vs. 64.4% respectively). Further investigations of the efﬁcacy and safety of higher doses of rivastig- mine (13.3 mg ⁄ 24 h, AUC24 h = 312 ngÆh ⁄ ml) are ongoing. Transdermal administration typically carries with it the risk of additional AEs not associated with oral administration, such as application site skin irritation and sleep disturbances (because of 24-h drug delivery). However, during the IDEAL trial no new safety issues were reported. In addition, the adhesion of the patch was very good, despite patients being permitted to pursue all normal daily activities including bathing and swimming. Skin irritation was actively assessed by the investigator or caregiver, yet most patients experienced ‘no, slight, or mild’ skin irritation (90–98% across all patch doses), with < 2.5% of patients in any treatment group discon- tinuing because of adverse skin reactions (19). Clinical experience suggests that the most common form of skin irritation is erythema caused by removal of the patch, which normally resolves after a short period of time (20). In the IDEAL trial, the signs or symptoms that were most frequently reported as moderate or severe were erythema (redness; 8% for the 9.5 mg ⁄ 24 h rivastigmine patch, up to 4% for placebo) and pruritus (itching; 7% for the 9.5 mg ⁄ 24 h rivastigmine patch, up to 3% for pla- cebo) (19). As stated previously (and in addition to the lower back), Lefe`vre et al. (17) demonstrated that the application of the rivastigmine transdermal patch to the upper arm, chest or upper back is least likely ª 2009 The Authors Journal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 799–805