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Dementia
Figure 1: Modelling Analysis Adjusted for
As with all transdermal medications, a concentration gradient is required
Gender and Bodyweight
18
to drive the diffusion of rivastigmine through the skin and into the
bloodstream. Therefore, it is necessary to load the patch with more than
25
Capsule 6mg BID
the required dose. In a study of 51 healthy men and women, both
Patch 9.5mg/24-hour
20
recommended sizes of rivastigmine patch released approximately 50% of
their total drug load over a 24-hour period (5cm
2
patch released 4.6mg
15
[51%]; 10cm
2
patch released 9.5mg [53%]).
17
c
entration (ng/ml)
c
on
10
The results from an open-label study of 51 AD patients randomised to a
astigmine 5
rivastigmine patch (4.6–17.4mg/24-hour) or capsules (3–12mg/day)
17
Riv
were used in a compartmental modelling analysis to predict rivastigmine
0
exposures over a single 24-hour application period (see Figure 1).
18
This
0 6 12 18 24
Time (hours)
analysis incorporated adjustments for baseline demographic differences
25 such as bodyweight and gender, and demonstrated that the target-dose
Capsule 3mg BID
Patch 4.6mg/24-hour
(9.5mg/24-hour) patch provides comparable drug exposure to the
20
highest recommended dose of capsules (12mg/day).
18
Since drug
exposure corresponds to efficacy, these data predict similar efficacy for
15
the target-dose rivastigmine patch and 12mg/day capsules. The
c
entration (ng/ml)
c
on
10 4.6mg/24-hour rivastigmine patch was shown to provide similar exposure
to 6mg/day capsules, which is considered to be an effective therapeutic
5
astigmine dose.
19–21
These results suggest that patients undergoing rivastigmine
Riv
patch therapy are initiated on an effective dose, and then titrated directly
0
0 6 12 18 24 to the target dose in a single step. The analysis also demonstrated that
Time (hours)
the 4.6mg/24-hour patch and the 9.5mg/24-hour patch provided
smoother and more continuous delivery of rivastigmine versus doses of
Steady-state rivastigmine plasma levels for a typical patient following application of the
9.5mg/24-hour patch versus 12mg/day capsules, or the 4.6mg/24-hour patch versus capsules with comparable exposure (6 and 12mg/day, respectively).
18
6mg/day capsules.
Both patches demonstrated significantly lower C
max
and longer t
max
(see
Figure 1), substantially reducing rivastigmine plasma fluctuations, thereby
Figure 2: The Recommended Procedure for Switching from
Oral Rivastigmine to Rivastigmine Patch Treatment
predicting an improved tolerability profile versus capsules.
What dose of oral rivastigmine is the patient receiving?
Clinical Data – Efficacy and Tolerability of the
Rivastigmine Patch
Clinical evidence for the efficacy and tolerability of the rivastigmine patch
was provided by the Investigation of transDermal Exelon in ALzheimer’s
disease (IDEAL) study. This was a 24-week randomised, double-blind
≤6mg/day* >6mg/day*
study in 1,195 mild to moderate AD patients from 21 countries, followed
by a 28-week open-label extension (n=870). Full details of the IDEAL
study have been published previously.
22–25
During the double-blind study, the 9.5mg/24-hour rivastigmine patch
Switch to 4.6mg/24-hour
Switch directly to target- demonstrated similar efficacy to the highest recommended doses of
rivastigmine patch
dose 9.5mg/24-hour
rivastigmine patch
rivastigmine capsules, with three times fewer reports of nausea or
vomiting.
22
Nearly all (96%) patients randomised to 9.5mg/24-hour patch
treatment reached their target dose compared with 64% of patients in the
* Regional differences in guidelines apply. The figure above represents the current
recommended switching guidelines in Europe (if a dose of 9mg/day is not stable or well
12mg/day capsule group.
26
Skin tolerability was good, with ≤2.4% of
tolerated, it is recommended to switch to 4.6mg/24-hour patch).
patients in any treatment group discontinuing due to adverse skin
reactions. No further new or unexpected tolerability or safety concerns
e.g. hairy or sensitive areas. In a recent open-label application study of 40 were reported.
22
Skin adhesion was good, despite normal activities being
healthy men and women 40–80 years of age, the pharmacokinetics, permitted (including bathing), and some study centres being located in
adhesion and skin tolerability of the rivastigmine patch were assessed at warm climates where perspiration might have been expected such as Chile,
five suitable application sites: upper back, upper arm, chest, abdomen and Venezuela or Israel. In 96% of the 1,336 evaluations of the 9.5g/24-hour
thigh. Optimal rivastigmine exposure (greatest AUC
24h
) was shown to patch, care-givers reported that the patch was completely attached or “had
occur when the patch was applied to the upper back, upper arm or chest the edges just lifting off” following the 24-hour application period.
22
(122, 116 and 123ng·hour/ml, respectively).
16
The t
max
remained slow
(over eight hours) irrespective of the application site investigated. The Results from the 28-week open-label extension study demonstrated the
overall skin tolerability was good during this study. Based on these safety and tolerability of the 9.5mg/24-hour rivastigmine patch treatment
findings, it is recommended that the rivastigmine patch be applied to up to one year, while providing sustained cognitive and functional
clean, dry, hairless skin on the upper back, upper arm or chest. benefits.
25
Similar to the double-blind study, skin tolerability during the
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