July 2005 July 2005 effectiveness zThe Novolizer® is robust, can be used every day, twice a day for...

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- 1 -www.alergomurcia.comJuly 2005

Novolizer®Technical Aspects

Dr JosDr Joséé MMªª Negro AlvarezNegro Alvarez

H.U. H.U. ““Virgen de la ArrixacaVirgen de la Arrixaca””. Murcia (Espa. Murcia (Españña)a)

Profesor Asociado de AlergologProfesor Asociado de Alergologíía. Universidad de Murcia (Espaa. Universidad de Murcia (Españña)a)


Contents

Design and function of the Novolizer®

Performance and efficacy, characteristics, robustness and reliability– in-vitro– in-use

Conclusions

2


Features of the Novolizer®

Easy and safe handling– Multiple feed back mechanism (audible, visual, sensoric)– Low intrinsic resistance – System preventing inadvertent multiple dosing– Dose counter linked to correct inhalation– Pocket-sized– No ingression of microorganisms

Excellent accuracy / precision– Consistent dose metering and delivery– Relative independence of particle size on flow rate– Ensured deposition of therapeutic agent in the bronchial tree– High respirable fraction, good efficacy– Reliable and durable

Advanced technology– Multidose– Unique and superior dispersion system


Cartridge

Powder

Dosing channel

Dosing chamber

Novolizer® - What’s in there ? (1)

3


Mouth piece

Powder channel

Dosage button

Tapper


Dosing scheme and inhalation mechanism


Cyclone

Laminar flow


4


Assured asthma drug delivery

Remove cap

Press the dosage button- patient hears a double click- colour change in inhalation window from red togreen

Inhale deeply- a ‘click’ indicates drug has been released

Guaranteed drug deposition in the lungs

There is only one way to use the Novolizer® ...... the right way !


Operation of the Novolizer® (1)

Press dosage button (dosage counter will be activated)

Device is ready for inhalation: colour change in inhalation window fromred to green

5


Operation of the Novolizer® (2)

Inhale with maximum inspiratory effort(deeply and strongly, only an inspiration >35 l/min is necessary)

Inhalation was successful: color change from green to red

Cover mouth piece with cap


Easy cartridge change

Remove slide cap

Remove empty cartridge

Replace with new cartridge

Replace slide cap

6


Multiple control feedback mechanism

Indicates successful inhalation

Guarantees inhalation of a correct & exact single dose, providing the patient with confidence, security, assurance and reassurance


Easy to use for most asthmpatients

Conclusion:The Novolizer is easy to use even for those patients with a reduced inspiratory flow rate (e.g. children and elderly people)

7


Dispersion system of the Novolizer®

The Novolizer® has a very effective deaggregation system

The cylcone:- Improves separation of particles- Improves flow of particles into thebronchial tree

- Minimises oropharyngeal deposition


Berner B et al., ASTA Medica Multidose Dry Powder Inhaler. In: Respiratory drug delivery VI. Dalby RN et al. (eds.), Buffalo Grove: Interpharm Press, 1998, 475-477

Conclusion: The Novolizer® exhibits excellent metering performance over the cartridge lifetime independent of temperature and humidity

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

0 50 100 150 200

Specification limits

Cartridge 1 (25°C/60% sealed)

Dose No.

Met

ered

mas

s [m

g]

Cartridge 2 (25°C/60% not sealed)Cartridge 3 (30°C/70% sealed) Cartridge 4 (30°C/70% not sealed)

Uniformity of metered mass: budesonide 200 µg formulation

8


Budesonide 200 µg formulation (nominal mass = 10.0 mg)flow rate corresp. to a pressuredrop of 4 kPa

Conclusion: The Novolizer® exhibits excellent emitting performance. The respirable fraction(FPF) is relatively independent on flow rate

Flow rate (l/min)

10.49.1

24

3428

0

2

4

6

8

10

12

14

16

40 60 80

Emitt

ed m

ass

[mg]

0

10

20

30

40

50

60

70

80

90

100

%B

udes

onid

e ca

lcul

ated

on

the

emitt

ed m

ass

Emitted mass Cascade 3-5 (FPF)

10.5

Emitted mass and fine particle fraction at various flow rates


0

10

20

30

40

50

60

70

80

90

100

110

120

0 3 6 9 12 18Months

Del

iver

ed d

ose

/fin

e pa

rtic

le d

ose

[in %

of

nom

. dos

e]

0102030405060708090100110120130140150160170180

Emitt

ed m

ass

[in %

of n

om. v

alue

]

Stored at 25°C/60%, 30°C/70%, 40°C/75% - sealed

Conclusion: The Novolizer® ensures stability under all tested climatic conditions

Stability testing: budesonide 400 µg

9


Design of the consumer test

Novolizers included in the study– 10

Duration of the study– 100 days

Applications– 2 actuations daily per inhaler (200 actuations per inhaler total)

Investigation parameters– Emitted mass: daily determination (Monday to Friday)– Delivered dose: weekly determination– Fine particle fraction: weekly determination


Dose No.0 50 100 150 200

%of

the

nom

inal

val

ue

0

20

40

60

80

100

120

Fine particle fraction

Delivered doseEmitted mass

Budesonide 200 µg formulation

Conclusion: The Novolizer® produces stable emitted mass, delivered dose and FPF over the lifetime of the cartridge

The Novolizer® consumer test results

10


DesignMicrobiological study: Novolizer® 1-Year in-use test

Placebo controlled

Group 1 (n=3)– Two actuations daily according to instructions for use (n=3)

Group 2 (n=3)– Two actuations daily,– Only 1 inhalation,– One dose remains in the device (n=3)

Group 3 (n=4)– Two actuations daily under worst case conditions

– Inhalation or blowing into the device,– Storage in bathroom, kitchen, outside, ...


Berner B et al. In: Proceedings of the 46th Annual Congress of APV/APGI, 2000

Conclusion: the microbial status of the cartidges and inhalers afer use is excellent

* Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Salmonella species,Enterobacteriaceae

Timepoint Total viable Moulds/ Specific[months] aerobic count Yeasts microorg.*

[cfu]

3 < 1 < 1 not detect.




Cartridges

ResultsMicrobiological study: Novolizer® 1-Year in-use test

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Time [sec]

0,2 0,6 1,0

Flow [l/min]

60

30

0,4 0,8

The Novolizer® ensures deposition of drug into the bronchial tree

Unique flow trigger valve- releases powder only after a certain flow ratehas been achieved (I.e. 35 l/min)

Represents a real step forward in DPI technology

Assured delivery = reassured patient

The Novolizer® releases sufficient powder, followed by the desagglomaration of the effective drug form the lactose carrier at a minimum inspiratory flow rate of 35 l/min

The Novolizer® is forgiving of poor technique


Budesonide200 µg formulation (nominal mass = 10.0 mg)

Flow rate (l/min)

10.49.1

24

3428

0

2

4

6

8

10

12

14

16

40 60 80

Emitt

ed m

ass

[mg]

0102030405060708090100

%B

udes

onid

e ca

lcul

ated

on th

e em

itted

mas

sEmitted mass Cascade 3-5 (FPF)10.5

Novolizer®: relative independence of particle size on flow rate

Consistently emits 90% of the metered dose

Little variation in emitted mass and FPF even when flow rates are halved

90% of particles are

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0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

0 50 100 150 200

Specification limits

Cartridge 1 (25°C/60% sealed)

Dose No.

Met

ered

mas

s [m

g]

Cartridge 2 (25°C/60% not sealed)Cartridge 3 (30°C/70% sealed) Cartridge 4 (30°C/70% not sealed)

Novolizer®: influence of temperature and humidity

Conclusion: Uniformity of emitted mass of drug from the Novolizer® is not influenced by varying conditions temperature and humidity


Low intrinsic resistance

Lower airflow resistance to Turbuhaler®

- Assuming a flow rate of 60 L/min, resistance is two times higher with Turbuhaler®

Easy for patients to use

Suitable for most patients even those with reduced inspiratory flow rate

May improve patient compliance

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Cost effectiveness

The Novolizer® is robust, can be used every day, twice a day for up to one year before it needs to be replaced

The Novolizer® is refillable

The most expensive inhaler is one that patients cannot use correctly- Novolizer® = assured drug delivery


Improved patient compliance

The multiple control system positively reinforces to the patient that medication has been taken

The dose counter works indirectly only after a correct inhalation- Positive reinforcement to patients that drug has been taken- Doctor can count how many doses have been taken

The Novolizer® is easy to use- It has a low intrinsic resistance- Patients are guided through the inhalation procedure by the triple control system

Patients are extremely satisfied with the Novolizer® (Kunkel and Chuchalin,2001)

The Novolizer® is pocket-sized and easy to carry

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Award: golden safety material in medicine

Acknowledges the unique position of the Novolizer®

Confirms that the Novolizer®

represents a new standard in inhalation devices

Supports introduction of new standard in safe inhalation technology


Eur Respir J 2000; 16: 178-183

Newman et al, 2000 - deposition

MethodGamma scintigraphic evaluation14 healthy volunteers (males/females)

Target parameterIn vivo deposition of a dry powder formulation from the Novolizer® at various flow rates versus the Turbuhaler®

Clinical Aspects

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Lung

Oropharynx

Device

Exhaled Air

32.1

57.0

9.5

0.8

(9.4 - 41.0)

(45.1 - 81.7)

(5.5 - 23.2)

(0.2 - 1.8)

25.0

61.6

15.6

0.6

(12.1 - 37.4)

(42.2 - 77.6)

(1.2 - 20.0)

(0.2 - 3.0)

19.9

60.9

17.3

0.2

(8.8 - 26.6)

(49.5 - 68.3)

(11.8 - 43.0)

(0 - 0.9)

21.4

71.9

11.6

0.2

(4.7 - 29.2)

(54.8 - 80.0)

(5.3 - 22.0)

(0 - 0.7)

Regimen% of metered dose; medians (ranges)

HeadlineHeadline

Novolizer®90L/min

Novolizer®60L/min

Novolizer®45L/min

Turbuhaler®60L/min

Eur Respir J 2000; 16: 178-183

Newman et al, 2000 - fractionation of dose (n=13) vs Turbuhaler®

Clinical Aspects


Novolizer®90L/min

0

5

10

15

20

25

30

35

40

Lung

dep

ositi

on[%

met

ered

dos

e]

Novolizer®60L/min

Novolizer®45L/min

Turbuhaler®60L/min

Newman et al, 2000 - lung deposition vs Turbuhaler®

At least as much deposition when used at similar rates

When used optimally the Novolizer® deposits more in lungs

Turbuhaler® deposits more drug in the mouth

Clinical Aspects

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Conclusion:

Novolizer®90L/min

Novolizer®60 L/min

Novolizer®45 L/min

Turbuhaler®60 L/min

Superiority of the Novolizer vs Turbuhaler® due to better drug deposition with less airflow resistance

Novolizer® : Lung deposition

Clinical Aspects


Turbuhaler® = uncertainty

Novolizer®

Precise dose delivery (FPF 30%)

Flow trigger valve

Guarantees sufficient drug deposited in lungs

Significantly better lung deposition

Turbuhaler®

High dose variation

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Equivalence study outline

Design– Randomized, open, multicenter parallel group study.

Centers– 11 centers

Patients– 315 asthmatics (224 female, 91 male; 18-75 years of age)

Inclusion criteria– Persistent mild-to-moderate asthma, FEV1: 60-90% predicted;

>15% reversibility; patients with regular pretreatment except steroids and patients on steroids

Treatment– 2 weeks run-in phase followed by 400 µg/d BUD (200 µg every 12 hours) delivered by either the

Novolizer® (n=153) or Turbuhaler® (n=158)

Kremer HJ et al. In: Scheuch G et al. Aerosole in der Inhalationsth. IV. Dusin: München, 2001; Chuchalin et al., Respiration 2002; 69: 502-508

Equivalence Study Budesonide 200 Novolizer® vs Pulmicort® Turbuhaler®


Target parameters

Primary efficacy parameter– FEV1 after 12 weeks of treatment

Secondary efficacy parameters– PEFR morning and evening, – Circad. PEFR variability, – Asthma symptoms, nocturnal awakening, – Use of ß2-agonists– PC20FEV1 after histamine provocation, – Assessment of efficacy

Safety– AEs (incidence, severity)– Cough and paradoxical bronchospasm, – Laboratory, ECG, RR, HF, opthalmological screening


Clinical Aspects


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Efficacy results

Primary target parameters– Mean FEV1 baseline values and improvement in FEV1 at the end of the study were comparable for

the Novolizer® and Turbuhaler®

Secondary target parameters– No clinically relevant or statistically significant differences between the groups were observef for:

PEFR (morning and evening), asthma symptoms, nocturnal awakening or rescue medication use– Histamine provocation test: essential differences between patients with or without pretreatment

with steroids, however, no significant differences between the Novolizer® and the Turbuhaler®groups.

– Global assessment of efficacy: investigators considered the efficacy of treatment to be ‚good‘ or‚very good‘ in 87% of patients in the Novolizer® group compared to 79% of patients in the Turbuhaler® group.

When delivering budesonide, the Novolizer® is therapeutically equivalent to the Turbuhaler® with respect to efficacy in mild-to-moderate asthmatics


Clinical Aspects



Safety and tolerability results

Paradoxical bronchospasmFEV1 decrease within 15 minutes after inhalation

– Novolizer® group (4)– Turbuhaler® group (6)

Incidence of adverse events– comparable in both groups

Blood pressure, heart rate, ECG, opthalmological examinations and laboratory values– No signs of clinically relevant adverse reactions or differences between groups

When deliverying budesonide, the Novolizer® is therapeutically equivlaent to the Turbuhaler®

with respect to safety and tolerability in mild-to-moderate asthmatics


Clinical Aspects


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250

300

350

400

450

Week

PEFR

[l/m

in]

Novolizer morning Turbuhaler morning

Novolizer evening Turbuhaler evening

1-2Baseline 3-4 5-6 7-8 9-10 11-12

Results (1)


Clinical Aspects



0

1

2

3

4

Salb

utam

ol p

uffs

Novolizer Turbuhaler

Week1-2Baseline 3-4 5-6 7-8 9-10 11-12

Results (2)



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1,5

2

2,5

3

3,5

0 4 8 12Week

FEV1

[l]

Novolizer Turbuhaler0

0,1

0,2

0,3

0,4

0,5

0 4 8 12Week

FEV1

chan

ges

vs

basi

slin

e va

lues

[l]


250

300

350

400

450

Base

line

1-2 3-4 5-6 7-8 9-10

11-12

Week

PEFR

[l/m

in]

Novolizer morning Turbuhaler morningNovolizer evening Turbuhaler evening

0

1

2

3

4

Base

line

1-2 3-4 5-6 7-8 9-10

11-12

Week

Salb

utam

ol p

uffs


Course of FEV1 FEV1 changes

Course of PEFR Course of Salbutamol consumption

(morning and evening)

Results (3)




Features

Drug deposition in the lungs even at low flow rates

Easy handling

Suction power required for inhalation

Multiple feedback mechanisms

Correct inhalation manoeuvre feedback

Accurate dosage counter

Display of readiness to inhale (green field)

Refillable

Novolizer®

low -to-moderate

Turbuhaler®

-

( )

high

-

-

-

-

-

Data on file

Novopulmon® 200 Novolizer®

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Pressure and flow comparison (1): Novolizer® vs Turbuhaler ®

Comparison of patient technique and inspiratory characteristics of the Novolizer® and the Turbuhaler®

60 patients with mild asthma

Patients had never used a dry powder device previously

Inhalation of placebo at least twice by Novolizer® or Turbuhaler®, respectively

Cegla, ERS 2002, Stockholm


Flow rate not reached

Novolizer®(n)

Turbuhaler®(n)

30 l/min 0 3

60 l/min 8 25

N = 60


Pressure and flow comparison (2): Novolizer ® vs Turbuhaler ®

Conclusion: More patients were unable to generate a peak inspiratory flow of either 30 l/min or 60 L/min through the Turbuhaler® compared to the Novolizer®

Novolizer® vs Turbuhaler® (Prof. Cegla, Dernbach)

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0.375

1.336

0.770

1.450

5.071

0.569

0.905

0.333

1.494

28.453

Time to max. pressure (s)

Peak flow (l/s)

Time (s) flow >60 l/min

Time (s) flow >30 l/min

Resistance (cm H2O.s/l)

Parameter Novolizer®(n)

Turbuhaler®(n)


Pressure and flow comparison (3): Novolizer ® vs Turbuhaler ®

Conclusion: Overall, the Novolizer® has a better inhalation performance to the Turbuhaler®

Novolizer® vs Turbuhaler® (Prof. Cegla, Dernbach)


Can children use the Novolizer®?

Aim: to determine if children aged between 4 and 11 years withstable bronchial asthma are ableto generate sufficient peak inspiratory flow (PIF) through the Novolizer®?

136 children. Multicenter, randomised, open label study design

Parameters assessed- FEV1- PIF withouth the Novolizer®

- PIF with the Novolizer® (PIF-N)

Leupold et al., ERS 2002, Stockholm

PIF Values in Children suffering from asthma (Prof. Leupold, Dresden)

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Leupold et al., ERS 2002, Stockholm

Results: can children use the Novolizer®?

Without the Novolizer® children could generate a PIFof 147 ± 46 L/min (mean ± SD)

With the Novolizer children could generate a PIFof 76 ± 19 L/min (mean ± SD)

Both PIF and PIF-N showed a linear dependence on age (older children could generate higher values)

The threshold value for activating the Novolizer® (i.e. 30 L/min) was exceeded by >40 l/min

The high PIF-N generated by children is due to the low-to-medium resistance of the Novolizer®

Conclusion: the Novolizer® is suitable for inhalation therapy in asthmatic children



40

60

76

86 83

0

10

20

30

40

50

60

70

80

90

100

Triggerthreshold

4 - 5years

6 - 7years

8 - 9years

10 - 11years

PIV-

N (l

/min

)

Conclusion: The Novolizer® is suitable for inhalation therapy in children aged 4-11 years with stable asthma

Leupold et al., Clinical Evaluation of the Peak Inspiratory Flow Generated by Asthmatic Children Through the Novolizer, Eur Respir J 2002; 20 Suppl 38: 430s

Trigger threshold of the Novolizer® and PIF-N by age inchildren with stable asthma


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Study Outline

Aim: to investigate the maximum inspiratory flow which children with stable asthma can achieve during inspiration through the Novolizer® compared to the Turbuhaler®

48 children aged between 4 - 11 years with stable asthma

Parameters assessed- FEV1, - PIF (without device)- PIF-N (Novolizer®)- PIF-T (Turbuhaler®)

Conclusion: The trigger threshold for activating the Novolizer® (i.e. 30 L/min) was easily exceeded by children aged between 4-11 years with stable asthma. The PIF generated through the Novolizer® was significantly higher than the PIF generated through the Turbuhaler® for allage groups studied

van Berg, et al, Eur. Respir. J. 2003

Novolizer® vs. Turbuhaler®: Clinical Study of Maximum Inspiratory Flow in Children


Age [y] N PIF[l/min]

PIF-N PIF-T PIF-N/T-ratio

4-5 2 78.9 ± 14.0 72.3 ± 5.5 57.9 ± 11.5 1.26 ± 0.15

6-7 16 150.2 ± 46.7 82.6 ± 16.7 62.3 ± 13.1 1.33 ± 0.10

8-9 14 186.3 ± 69.5 100.6 ± 16.4 74.7 ± 10.7 1.36 ± 0.20

10-11 16 217.8 ± 59.0 98.4 ± 18.8 71.7 ± 12.2 1.37 ± 0.14

All 48 180.3 ± 66.2 92.7 ± 18.9 68.9 ± 13.0 1.35 ± 0.15

PIF-N was significantly higher than PIF-T in all age groups (p

25


0

20

40

60

80

100

120

Triggerthreshold

all patients

6 to 7years

8 to 9years

10 to 11years

L/m

inPIF-T PIF-N

PIF-N and PIF-T for different age groups

New Clinical Data: Novolizer and Ease of Use in Severe Asthma

Inhalation Inspiration Innovationvan Berg, et al, Eur. Respir. J. 2003


Post Marketing Surveillance (PMS) in Patients with Bronchial Asthma

Novolizer® budesoinde 200 µg

Scope: 3057 patients in 963 centers

Collection of data on clinical efficacy, tolerability and patient acceptance of the device

Patients with or without inhaled asthma pretreatment

Duration of observation per patient: 4 weeks

Parameters assessed– Lung function (PEFR, FEV1)– Symptoms (cough, rhonchus, nocturnal dyspnea, dyspnea on exertion)– Satisfaction with control functions– Assessment of patient compliance by the treating physician

Moeller et al, Drug Research 53, No 8, 562-567, 2003

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Novolizer® budesonide 200µg: results (1)

Parameters of lung function– Median PEF increased from 5 Ll/s to 6.3 L/s– Median FEV1 increased from 2250 ml to 2700 ml

Symptoms improved in most patients- Median symptom score fell from 8 before therapy to 2 after therapy

The proportion of patients complaining of each assessed symptom decreased– Cough: 93.0% at baseline to 56.5% post-treatment– Wheezing: 87.9% at baseline to 37.9% post-treatment– Diurnal dyspnea: 87.2% at baseline to 40.3% post-treatment– Nocturnal dyspnea: 80.5% at baseline to 37.0% post-treatment– Dyspnea on exertion: 97.3% at baseline to 75.2% post-treatment





Satisfaction with multiple inhalation control features (all patients)– 62% of the patients: excellent– 37% of the patients: good

Satisfaction with multiple inhalation control features(patients pretreated with other inhalation system before)

– 93% of the patients: better / much better– 96% of the patients reported better compliance due to the control mechanisms

Assessment by the treating physicians– Improvement of compliance due to control mechanisms in 98% of the patients– Better control of compliance was rated by 95% of the physicians


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Control of drug intake by different control mechanisms was confirmed by 97% of patients– 88%: optical control mechanism– 81%: acoustic control mechanism– 46%: taste control mechanism

Dose counter control– 92% of the patients were satisfied with the counter– 81% of the patients assessed the dosage stop as „good“– 79% of the patients were pretreated with another inhalation system, (Diskus® and Turbuhaler®)-

Evaluation will follow

Novolizer® budesonide 200µg proved to be clinically effective with high acceptance of thecontrol functions and improved compliance



Novolizer®: Clinical Aspects

Commonly prescribed DPIs vs Novolizer®

Easy, reliable & convenient to use

Easy to teach, learn & remember how to use correctly

Accurate & consistent dose delivery

High deposition rate

Patient feedback of dose taken

Accurate dose counter

Delivers a range of molecules

CFC-free & conveniently carried

Certainty given to patient and doctor

Novolizer´sfeatures TH Diskus Aerolizer

/ -

-

-

-

-

-

-

-

-

-*

-

-

-

-

-

-

-*

-

-

* taste only

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Novolizer®: Clinical Aspects

Gina Guidelines 2002

Novolizer therapies cover all levels of asthma severity

Level of Severity (US est. Diagnosed cases* (16M) )

Daily Medications Quick Relief &Prevention **

Intermittent Asthma (7M) none necessary

Mild Persistent Asthma (3M) glucocorticosteroid

Moderate Persistent Asthmaglucocorticosteroidlong-acting ß2-agonist

Severe Persistent Asthmaglucocorticosteroid

+ - sustained-release theophylline- leukotriene modifier - long-acting oral ß2-agonist- oral glucocorticosteroid

one or more if neededalso recommended for prevention of exercise induced asthma* Decision Resources, NHIS, ALA Reports

(3M)

(3M)long-acting ß2-agonist

**

short-actingß2-agonist




+

July 2005 July 2005 effectiveness zThe Novolizer® is robust, can be used every day, twice a day for...

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