1. Roflumilast: profilo di sicurezza e tollerabilità1

2. Roflumilast: il profilo di tollerabilità emerso dagli studi clinici
Side effects associated with roflumilast therapy were typically mild to moderate
They occurred mainly within the first weeks of therapy and mostly resolved on continued treatment
Changes in weight, and neuropsychiatric events should be monitored
Most commonly reported adverse reactions*
Diarrhoea
5.9%
Weight decrease
3.4%
Nausea
2.9%
Abdominal pain
1.9%
Headache
1.7%
Speaker notes
In clinical studies, approximately 16% of patients taking roflumilast experienced adverse reactions compared to 5% of patients taking placebo.
The most commonly reported adverse reactions were diarrhoea, weight decrease, nausea, abdominal pain and headache. The majority of these adverse reactions were mild or moderate. They occurred mainly within the first weeks of therapy and mostly resolved with continued treatment.
Changes in weight and neuropsychiatric events should be monitored when taking roflumilast.
Body weight of underweight patients should be checked at each visit. Patients should be advised to check their body weight on a regular basis and record the results on the patient information card. In the event of an unexplained and clinically concerning weight decrease, intake of roflumilast should be discontinued and body weight should be further followed up.
Physicians and patients should be informed of the higher incidence of neuropsychiatric events associated with roflumilast, including rare events of suicidal behaviour. Patients should be monitored for changes in neuropsychiatric events.
Reference
Daxas® European Summary of Product Characteristics. Available at the end of this slide kit and at
*Expressed as percent of total study population
Daxas® EU SmPC. Available at 2

3. Eventi avversi severi (SAE)
COPD safety pool
placebo (N=5,491)
(%)
rof500 (N=5,766)
All SAEs
14.2
13.5
COPD exacerbation
7.1
5.8
Pneumonia
1.1
Atrial fibrillation
0.2
0.4
Myocardial infarction
Chest pain
0.3

4. Eventi avversi associati a morte
COPD safety pool
placebo (N=5,491)
n (%)
rof500 (N=5,766)
All deaths
86 (1.6)
84 (1.5)
AE associated with deaths*
COPD
22 (0.4)
20 (0.3)
Pneumonia
10 (0.2)
9 (0.2)
Cardiac arrest
1 (<0.1)
7 (0.1)
Acute respiratory failure
4 (<0.1)
6 (0.1)
Sudden death
6 (<0.1)
Speaker notes
In the 6-month clinical study in which patients received roflumilast or placebo in addition to tiotropium, the mean weight decrease was 2.1kg more in the roflumilast group compared with placebo group (95% CI -2.5, -1.7; p<0.0001).1,2
BMI fell gradually in roflumilast-treated patients, until reaching a plateau at 18 weeks of treatment (mean decrease 0.73 kg/m2). No significant change in BMI was observed in patients taking placebo during the 24-week treatment period (mean decrease 0.03 kg/m2).2
The overall mean difference in BMI between roflumilast-treated and placebo-treated patients was –0.76 kg/m2 (95% CI –0.89, –0.62; p<0.0001).2
Bioimpedance measurements indicated only minimal changes in fat free mass index (FFMI) following roflumilast or placebo treatment. There was an initial decline in FFMI in the roflumilast group, but after approximately 4 weeks of treatment, no obvious further large (>0.2 kg) change was noted for either group. There was no significant difference between the change in FFMI in roflumilast-treated and placebo-treated patients (mean difference kg/m2, 95% CI to ; p=0.0059).2
These data indicate that the weight decrease associated with roflumilast was primarily fat mass and probably not owing to continued loss of muscle mass.
References
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703.
Wouters EFM, Teichmann P, Brose M, et al. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:A4473.
* Investigator reported 4

5. Concetti chiave
Adverse events were frequently reported but there was no overall difference in the number of events between treatment arms
There were no differences in the SAE event rate or in mortality with roflumilast
More people withdrew from the studies while taking roflumilast (5%) mainly due to GI effects 5

6. Eventi avversi gastrointestinali: la maggior parte si risolve in 4 settimane
Diarrhoea
Nausea
69%
resolved
74%
resolved
% patients
Speaker notes
Safety data from 14 placebo-controlled, double-blind, phase II/III studies of roflumilast 500µg once daily (n=5766) versus placebo (n=5491), in subjects with moderate to very severe COPD, were pooled and analyzed.
Apart from decreased weight, the majority of the most frequently reported AEs (such as diarrhoea and nausea) resolved within 4 weeks.
Reference
Gross N, Calverley P, Fabbri LM et al. Characterization of safety with roflumilast, an oral phosphodiesterase-4 inhibitor for the treatment of COPD Chest. 2010; 138:466A (Abstract+ Poster).
Roflumilast
Placebo
GI=Gastrointestinal
Adapted from Gross N, Calverley P, Fabbri LM, et al. Chest. 2010; 138:466A (Abstract+ Poster). 6

7. Diarrea 16 Diarrhoea SAEs in COPD safety pool
3 cases before start of treatment
COPD safety pool
placebo (N=5,491)
n (%)
rof500 (N=5,766)
rof250 (N=797)
All Diarrhoea AEs
143 (2.6)
585 (10.1)
39 (4.9)
Reported as SAEs
1 (<0.1)
10 (0.2)
2 (0.3)
SAE recovered 1
10* 2
7 cases recovered without discontinuing the study and continued roflumilast treatment 7

8. Roflumilast e perdita di peso
Noted as a self-reported finding more often with roflumilast
Not just confined to patients reporting GI intolerance
Monitored with regular weight measurement in pivotal one year trials
In one 6 month study bioimpedance data were available 8

9. La perdita di peso si manifesta nei primi 6 mesi di trattamento
Speaker notes
The average weight change in 12-month clinical studies was a loss of 2.09kg in patients taking roflumilast and a gain of 0.08kg in patients taking placebo.
This was a mean difference of 2.17kg more weight lost in patients taking roflumilast compared with patients taking placebo (95% CI -2.4 to -1.9, p<0.0001).1
Most of the weight decrease occurred in the first 6 months of treatment and was attenuated thereafter.1
In a 12-week follow-up study, patients who experienced weight decrease during the treatment phase were monitored for further changes in weight (n=126; roflumilast, 91; placebo, 35).
Most of the patients who were treated with roflumilast regained weight in the follow-up period, demonstrating that the weight decrease was reversible upon discontinuation of roflumilast treatment.2
References
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694.
Martinez FJ, Rabe KF, Wouters EFM, et al. Time course and reversibility of weight decrease with roflumilast, a phosphodiesterase inhibitor. Am J Respir Crit Care Med 2010;181:A4441.
Calverley PMA, Rabe KF, Goehring UM, et al. Lancet 2009;374:685–694. 9

10. La perdita di peso è più evidente nei pazienti obesi
Speaker notes
In a pooled analysis of the two 12-month clinical studies, patients were categorised based on body-mass index (BMI) as follows:
Underweight ≤18
Normal 18 to ≤25
Overweight 25 to ≤30
Obese >30 kg/m2.
The largest absolute weight decrease was observed in obese patients (BMI over 30 kg/m2) treated with roflumilast.
Reference
Calverley PMA, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive disease: two randomized clinical trials. Lancet 2009;374:685–694. (Supplementary webappendix)
Calverley PMA, Rabe,KF, Goehring, UM, et al. Lancet 2009;374:685–694. (supplementary webappendix). 10

11. La perdita di peso è a carico della massa grassa
Speaker notes
In the 6-month clinical study in which patients received roflumilast or placebo in addition to tiotropium, the mean weight decrease was 2.1kg more in the roflumilast group compared with placebo group (95% CI -2.5, -1.7; p<0.0001).1,2
BMI fell gradually in roflumilast-treated patients, until reaching a plateau at 18 weeks of treatment (mean decrease 0.73 kg/m2). No significant change in BMI was observed in patients taking placebo during the 24-week treatment period (mean decrease 0.03 kg/m2).2
The overall mean difference in BMI between roflumilast-treated and placebo-treated patients was –0.76 kg/m2 (95% CI –0.89, –0.62; p<0.0001).2
Bioimpedance measurements indicated only minimal changes in fat free mass index (FFMI) following roflumilast or placebo treatment. There was an initial decline in FFMI in the roflumilast group, but after approximately 4 weeks of treatment, no obvious further large (>0.2 kg) change was noted for either group. There was no significant difference between the change in FFMI in roflumilast-treated and placebo-treated patients (mean difference kg/m2, 95% CI to ; p=0.0059).2
These data indicate that the weight decrease associated with roflumilast was primarily fat mass and probably not owing to continued loss of muscle mass.
References
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lancet 2009;374:695–703.
Wouters EFM, Teichmann P, Brose M, et al. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:A4473.
FFMI = Fat Free Mass Index
BMI = Body Mass Index
Wouters EFM, Teichmann P, Brose M, et al. Am J Respir Crit Care Med 2010;181:A4473. 11

12. FORTUNA study: roflumilast e diabete di tipo 2
Mean change in HbA1c between baseline and last visit 12

13. Mean change in body weight [kg]
Studi M2-124 e M2-125: recupero del peso corporeo alla sospensione del trattamento
Double blind treatment period
FU period
Mean change in body weight [kg]
Speaker notes
Safety data from 14 placebo-controlled, double-blind, phase II/III studies of roflumilast 500µg once daily (n=5766) versus placebo (n=5491), in subjects with moderate to very severe COPD, were pooled and analyzed.
Apart from decreased weight, the majority of the most frequently reported AEs (such as diarrhoea and nausea) resolved within 4 weeks.
Reference
Gross N, Calverley P, Fabbri LM et al. Characterization of safety with roflumilast, an oral phosphodiesterase-4 inhibitor for the treatment of COPD Chest. 2010; 138:466A (Abstract+ Poster).
Time (weeks)
roflumilast, n=
placebo, n= 91 35 90 34 88 34 87 33 84 32 83 31
Martinez FM, et al.  Am J Respir Crit Care Med 2010;181:A4441. 13

14. Perdita di peso Weight loss occurs more frequently with roflumilast
Largest weight loss in obese patients but occurs also in underweight patients
Mainly loss of fat mass based on bioimpedance data
Evidence of reversibility after treatment discontinuation
No increased morbidity due to weight loss was observed in comparison to placebo
Weight should be regularly monitored in patients taking roflumilast 14

15. Complicanze cardiovascolari
No pre-clinical concerns for cardiac toxicity or conduction abnormalities
No QTc prolongation at doses up to 1,000 mcg
Holter monitoring did not show any difference between roflumilast and placebo (n=210)

16. Roflumilast: nessun aumento del rischio di mortalità cardiovascolare
COPD safety pool
placebo (N=5,491) (n=86*)
rof500/rof250 (N=6,563) (n=91*)
n (%)
Cardiovascular
42 (0.7)
35 (0.5)
Sudden death, etiology unknown
26 (0.4)
22 (0.3)
Death due to myocardial infarction
3 (<0.1)
4 (<0.1)
Death due to stroke
Sudden death due to arrhythmia
2 (<0.1)
1 (<0.1)
Death due to congestive heart failure
Other cardiovascular deaths
Non-cardiovascular
40 (0.7)
52 (0.8)
Insufficient data
Speaker notes
Safety data from 14 placebo-controlled, double-blind, phase II/III studies of roflumilast 500µg once daily (n=5766) versus placebo (n=5491), in subjects with moderate to very severe COPD, were pooled and analyzed.
Apart from decreased weight, the majority of the most frequently reported AEs (such as diarrhoea and nausea) resolved within 4 weeks.
Reference
Gross N, Calverley P, Fabbri LM et al. Characterization of safety with roflumilast, an oral phosphodiesterase-4 inhibitor for the treatment of COPD Chest. 2010; 138:466A (Abstract+ Poster).
* Number of Deaths
White WB, et al. Am J Respir Crit Care Med 183;2011:A3092. 16

17. Profilo di tollerabilità
No difference in the incidence of pancreatitis
No convulsions or ventricular arrythmias
No difference in the incidence of positive occult blood testing and no clinical cases of ischaemic colitis

18. Conclusioni We have a large data base about roflumilast
Roflumilast produces pharmacologically predictable side effects in some people - these are generally mild and self- limiting but some patients prefer to stop treatment
Weight loss occurs in some patients taking roflumilast - it is modest, not usually progressive and more marked in obese patients
There are no obvious concerns about overall mortality, pneumonia, cardiovascular or tumour-related events
There are insufficient data about risks in patients prone to suicide - better to use other treatments in these patients
Roflumilast has an acceptable and manageable safety profile in COPD patients

19. Concetti chiave
Roflumilast was generally well tolerated in clinical studies, with most side effects being mild to moderate and transient
Some patients experienced a weight decrease while taking roflumilast
Analyses have shown that the greatest weight decrease was experienced by patients with high BMI, was mainly due to loss of fat mass, and was reversible upon discontinuation of roflumilast treatment
Patients should be monitored for changes in body weight and neuropsychiatric events while taking roflumilast 19