India’s 1st extra-fine ICS-LABA

Niveoli inhaler
A unique offering from Cipla respiratory
Learning objectives
• Understanding small airways

• Diagnosing involvement of small airways in OAD

• Extra-fine formulations

• Niveoli: brand modalities

Understanding small airways
disease

Small airways disease:

What are small airways? Subjective & Objective
markers
 THE BRONCHIAL TREE

SMALL AIRWAYS
- < 2mm in diameter
- 28,000 in number
- No cartilage
- Smooth Muscles

The small airways of the lung are defined as the bronchial

passages less than 2 mm in diameter and located beyond the
7th or 8th generation of the tracheobronchial tree.
 Small Airways/peripheral airways/distal
airways

• They contribute to around 10-20%

of the total airflow resistance.

• Contain little or no cartilage-

easily collapsible

• Also called the ‘silent zone’ of the

lungs
 Evidence of small airways inflammation in asthma

Am J Respir Crit Care Med 2001;163:1551-56

Am J Respir Crit Care Med 1995;152:1784-90
Small airways dysfunction in COPD
Pathophysiology of COPD:
 Involvement of small airways in COPD

Normal small airway Abnormal small airway with

airway remodeling in COPD

The airway is narrowed

by deposition in the
interstitial space

CHEST 2011; 139(2):412–423

Subjective & Objective assessment small airway inflammation according to
availability…
 Objective Measures in the order of
specificity:
1. Impulse Oscillometry

2. Body
plethysmography
3. HRCT

4. Spirometry
Clinical Phenotypes that raise suspicion of small airways disease…

Poor asthma control with frequent risk of

exacerbations

Treatment Resistant asthmatics

Presence of nocturnal asthma

Severe bronchial hyperresponsiveness

Exercise induced bronchoconstriction.

Respir Med. 2016 Jul; 116:19-27

 Targeting small airways
Extra fine formulations
Importance of Particle Size of Inhaled Formulations..
Particle size Regional deposition Efficacy Safety Deposition forces
(aerodynamic
diameter in microns)

Mouth / oesophageal No clinical Absorption from Inertial Impaction

>5 region effect GI tract if
swallowed

Majorly Clinical Subsequent Sedimentation by

1–5 Upper/ Central & in effect absorption from gravity
alveolar airways (<2) lung

Majorly Peripheral Some local High systemic Brownian motion

<1 airways/ alveoli, easily clinical absorption
exhaled effect

Particles <2µm majorly deposit in the small airways, has reduced oropharyngeal
deposition and has a homogeneous deposition both in the small and large airways
J Aerosol Sci, 17 (1986), pp. 811-825
 Impact of particle size on lung deposition..

Mass Median Aerodynamic Diameter*

Triamcinolone CFC 22%
4 Budesonide DPI 16%
Flunisolide CFC 20%
Beclomethasone CFC 4%
3
Fluticasone HFA: unknown
Fluticasone HFA
Fluticasone CFC 13%
2
Ciclesonide HFA 52%
1 Beclomethasone 58%
HFA
0% 10% 20% 30% 40% 50% 60%
Lung Deposition

Chest. 2002;122:510-516. J Aerosol Med. 2006;19:117-126.

*The relationship between particle size (MMAD) and clinical efficacy is unknown. J Aerosol Med. 2005;18:379-385. J Aerosol Med. 2002;15:15-25.
The particle size of mometasone DPI is unpublished. J Allergy Clin Immunol. 2002;109:S447-S460.
Lung & oropharyngeal deposition with extra-fine
beclomethasone
 Lung deposition

Greater lung deposition with beclomethasone-

HFA compared to beclomethasone-CFC

Beclomethasone Beclomethasone
CFC HFA (small particle)
Lung
10%-20% 50%-60%
deposition
Oropharyngeal
>80% 30%-40%
deposition

Lung deposition with Lung deposition with

beclomethasone CFC beclomethasone HFA MDI
MDI
ɣ-scintigraphic lung images
Healthy (n=6) & mild asthmatics (n=16)
CFC: Chlorofluoro carbon CHEST 2011; 139(2):412–423
HFA: Hydrofluoro alkane Eur Respir J 1998; 12: 1346–1353
Extra-fine vs. non extra-fine beclomethasone

250 micrograms
100 micrograms
of beclometasone
of extra fine
dipropionate in a
beclometasone
non-extra fine
dipropionate
formulation

SPC, Fostair. EMC UK

Extra Fine formulation of Beclomethasone/Formoterol Combination

Lung deposition Efficacy Safety

 Lung deposition

Lung deposition with extra-fine

beclomethasone/formoterol

Mean lung deposition of nominal dose:

In healthy subjects: 34.08%
In asthmatics: 30.86%
In COPD patients: 33.10%
No significant difference within the groups

Healthy subjects (n=8), persistent asthmatics (n=8) & patients with stable COPD (n=8)
All received one single treatment of four puffs of BDP/F 100/6 mcg J Aerosol Med Pulm Drug Deliv. 2010;23(3):137-48
 Particle size distribution by mass (mcg) in both small
and large airways demonstrated by Cascade Impaction
INDUCTION PORT BECLOMETHASONE FORMOTEROL
DIPROPIONATE DIHYDRATE
Induction Port 46.07 2.96

S0 3.68 0.21

S1 0.99 0.06

S2 0.62 0.03

S3 1.87 0.11
Large airways S4 7.51 0.44

S5 14.28 0.85

S6 6.21 0.36
Small
airways S7 2.96 0.16
 Phase III, multinational, multicentre, double-blind
219 patients with moderate-to-severe asthma

12-week treatment with BDP/F 200/12mcg delivered via a

pMDI or budesonide/F 400/12mcg bd delivered via a DPI.

Clinical symptoms’ scores significantly decreased from baseline

in both groups from the first 2-week period onwards, as well as
daily use of rescue salbutamol, with no significant difference
between groups at the end of treatment

Eur Respir J 2007; 29: 682–689

Non inferiority of BDP/F vs Bud/F..

The new fixed combination of beclomethasone and formoterol inhaler is equivalent to the marketed
combination of budesonide and formoterol in terms of efficacy and tolerability profile Eur Respir J 2007; 29: 682–689
Therefore, extra fine BDP/F has proven
efficacy..

1. Deposition in both large and small airways

2. Switching from other ICS/LABA provides improved asthma
control in uncontrolled patients.
3. Effective in both smokers and non smokers
4. As efficacious as formoterol/budesonide in moderate to severe
asthma.
Safety of beclomethasone/formoterol
• Twenty-four-hour serum cortisol concentrations were significantly higher with BDP/F than with
BDP and formoterol administered separately (2.26 vs 1.90 mgh/mL; p < 0.01) indicating
absence of cortisol suppression.

• No significant differences in the pharmacokinetic parameters of formoterol and no clinically

relevant differences in serum potassium and cardiovascular or spirometric parameters were
observed between the treatments.
 Niveoli: Extra fine formulation
Beclomethasone dipropionate 100µg + Formoterol
fumarate 6µg
MRP PTS PTR
196.2 126.1 140.2
 Niveoli: Composition
Each actuation delivers:
Formoterol fumarate dihydrate IP……….6mcg
Beclomethasone dipropionate IP…………100mcg
Suspended in propellant HFA134a….........q.s

DOSAGE FORM: Pressurized inhalation solution; 120 metered doses

 Niveoli: Lung Deposition
In-Vitro studies conducted on Niveoli Inhaler (Beclomethasone dipropionate/formoterol pMDI, Cipla Ltd)
demonstrating particle size distribution by Cascade Impaction:

 
Beclomethasone Formoterol Fumarate
Dipropionate Dihydrate

MMAD(µm) 1.59 1.60

Lung 41.62 39.55

deposition(%)
Indications:
Asthma
• Niveoli Inhaler is indicated in the regular treatment of asthma where use of a combination product (inhaled
corticosteroid and long-acting beta2-agonist) is appropriate:

• - patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled rapid-acting beta2-agonist
or

• - patients already adequately controlled on both inhaled corticosteroids and long-acting beta2-agonists.

COPD
• Symptomatic treatment of patients with severe COPD (FEV1 < 50% predicted normal) and a history of repeated
exacerbations, who have significant symptoms despite regular therapy with long-acting bronchodilators.
Dosage & Administration:
ASTHMA
Maintenance therapy: Maintenance & Reliever therapy:

Niveoli Inhaler is taken as regular maintenance Dose recommendations for adults 18 years and
above:
treatment with a separate as needed rapid-acting
bronchodilator. 1 inhalation, twice daily
Patients should take 1 additional inhalation as needed
• Dose recommendations for adults 18 years and in response to symptoms.
above: The maximum daily dose is 8 inhalations.
• One or two inhalations twice daily. Niveoli Inhaler is not recommended for children
• The maximum daily dose is 4 inhalations. and adolescents under 18 years until further data
become available.

COPD
Dose recommendations for adults 18 years and above:
Two inhalations twice daily.
 Shelf Life
• Proposed shelf life of the product is 12 months when stored at 2-8⁰C and 3 months at 25⁰C.
Special Instructions for Pharmacists:
• Prior to dispensing to the patients, the Niveoli Inhaler should be stored in a refrigerator at 2 ⁰C to 8 ⁰C.
• It’s important to ensure that there is a period of at least 3 months between the date of dispensing and the expiry
date printed on the pack.
• The patients should be instructed to use the product within 3 months of purchase.
Storage Information for Patients:
• The product should be stored below 25⁰C.
• The Niveoli inhaler should not be exposed to heat or direct sunlight.
• The Niveoli Inhaler should not be exposed to humid or wet environment.
• If the inhaler has been exposed to severe cold, the canister should be taken out of the actuator and warmed with
hands for a few minutes before using. It should never be warmed by artificial means.
 Niveoli in team 2 MSL – Balancing the portfolio

OAD patient at GP: foracort/duolin OAD patient at physician: OAD patient at chest:
foracort/duolin niveoli inhaler/foracort

OAD patients with large airways OAD patients with small airways involvement: niveoli inhaler
involvement: Foracort

SMART therapy: Foracort Predominant nocturnal asthma: niveoli inhaler

Exercise induced asthma: niveoli inhaler

Core competitor prescriber: niveoli inhaler

Taper down from high dose of ICS in OAD: niveoli inhaler

ICS+LABA along with OCS prescribers: niveoli inhaler

 Niveoli : Key points to remember

• Probing and Discussion & NOT Reminder

• Dialogue on potential patient profile for Niveoli

• Important studies around small airways and extrafine ICS+LABA

• 3 Key USPs of brand

Precisely targeted delivery Proven efficacy Better safety profile

Deposition across large and small airways Comparable outcomes vs other Minimum local / systemic side effects
ICS+LABA combinations with the advantage of lower nominal dose
Refining
Asthma Management
with Ciclohale
(Ciclesonide)
Challenges with prescribing the conventional ICS formulations…

Concerns about ‘Steroids’

• Patients with persistent asthma often need long term high doses of steroids
• High dose of steroids does not always result in increased efficacy
• Higher doses of steroids might lead to potential side effects
• the risk of adverse events (AEs) associated with high dose ICS may make some physicians reluctant to increase
ICS dosage and
• Patients reluctant to adhere to the treatment
• Economic burden of chronic controller therapy

Patient perception

• Steroids do not provide immediate symptom relief

• Patients see ‘SABA’ as an effective treatment because of the instant symptom relief
• Patients have poor adherence to twice daily long term treatment with steroids

Arch Intern Med 1999; 159:941–955 Thorax. 2008 Sep; 63(9): 831–838.
Patient Preference and Adherence 2015;9:235-242.
 What is the need of the hour?
An ICS that deposits An ICS that improves
An ICS that is SAFE throughout the bronchial tree compliance

Long-term treatment with Traditional formulations of ICS Adherence to treatment is a

high doses of currently settle predominantly in the large major concern for patients in
available ICSs may still be airways, newer formulations with chronic conditions like asthma.
associated with local & an extra-fine particle size of
systemic adverse effects. <2microns have a more peripheral Having once daily ICS with a
pattern of deposition. broader safety margin than the
ones currently available, might
help address this concern

CHEST 2005; 128: 1081-1084

 Introducing the refined ICS - Ciclesonide
Ciclesonide des-Ciclesonide

Inactive prodrug Active metabolite

• A new generation inhaled glucocorticoid with high local anti-inflammatory properties.
• It is an ester pro-drug, which is hydrolyzed enzymatically by esterases to its active metabolite desisobutyryl ciclesonide in the lung

Drugs 2008; 68 (12): 1741-1770

Journal of Clinical Pharmacy and Therapeutics (2009) 34, 1–12
 SAFE? SINGLE? SMALL?

• On site activation • High lipophilicity • Extra fine solution formulation

• • Lipid conjugation • High lung deposition
Low oral bioavailability
• Low oropharyngeal deposition
• High plasma protein binding
• High systemic clearance

As efficacious as other ICSs

On site activation
 Low oral Bioavailability Clearance & half life
• Low oral bioavailability leads to less systemic side effects • Clearance is the measure of how efficiently a
• Low oral bioavailability (<1%) drug is irreversibly removed from the body
• Rapid clearance minimizes systemic side
effects
Negligible Oropharyngeal Effects

• Ciclesonide is inhaled in an inactive state and gets converted to its

active form only in the lungs
250
• Ciclesonide is formulated as an extra fine solution which
minimizes oropharyngeal deposition
200
High Protein Binding
150
• High protein binding results in lesser concentration of free unbound
drug in systemic circulation
100
• Only the free, unbound drug is pharmacologically active
• Protein bound drug is not available to cause systemic effects 50

0
BMP BUD FP CIC-AP
SINGLE?
 Prolonged Effect In Lungs: Enabling Once daily dosing

Lipid Conjugation High Lipophilicity

• Lipid conjugation allows an ICS to remain longer High lipophilicity

in the lungs

• Prolonging lung residence time increases the time Longer pulmonary residence time
an ICS interacts with its receptors in the lung

• Increased lung residence time may improve Prolonged exposure of drug to receptor
efficacy and safety
Increased anti inflammatory effect

Only Des-cic and Budesonide form highly

Ciclesonide > FP > des-CIC > BUD
lipophilic fatty acid conjugates.
Not seen with Fluticasone Propionate.

Eur Respir J 2006; 28: 1042–1050 Drugs 2008; 68 (12): 1741-1770

SMALL
 Impact of particle size on lung deposition..

Triamcinolone CFC 22%

Mass Median Aerodynamic Diameter*

4 Budesonide DPI 16%
Flunisolide CFC 20%
Beclomethasone CFC 4%

3
Fluticasone HFA Fluticasone HFA: unknown
Fluticasone CFC 13%

Ciclesonide HFA 52%

1 Beclomethasone 58%
HFA
0% 10% 20% 30% 40% 50% 60%
Lung Deposition

The MMAD of an aerosol refers to the particle diameter that has 50% of the Chest. 2002;122:510-516. J Aerosol Med. 2006;19:117-126.

aerosol mass residing above and 50% of its mass below it. J Aerosol Med. 2005;18:379-385. J Aerosol Med. 2002;15:15-25.
J Allergy Clin Immunol. 2002;109:S447-S460.

*The relationship between particle size (MMAD) and clinical efficacy is unknown. The particle size of mometasone DPI is unpublished.
 Deposition Across Large & Small airways

High lung deposition

• Formulated as an extra fine solution with aerosol
diameter of <2microns

(Ciclohale pMDI, Cipla Ltd) demonstrating

particle size distribution by Cascade Impaction:

  Ciclohale 80 Ciclohale 160

Inhaler Inhaler

MMAD(µm) 1.3 1.6

Anderson Cascade Impactor

Data on File 2019, Cipla Ltd.

 Summary: Properties of ciclesonide

On site activation High Potency Prolonged Effect In Lungs

• Ciclesonide is inhaled in • Des-CICLESONIDE has High Lipophilicity

an inactive form. a high relative • Ciclesonide is the most
• Ciclesonide has negligible glucocorticoid receptor lipophilic ICS.
binding affinity
oropharyngeal adverse
effects as it is present in • It is approximately 100 High Lipid conjugation
the inactive form in the times greater than that of • Prolongs lung residence time,
oropharynx and gets the parent compound, which maximizes pulmonary
activated only in the ciclesonide. effects.
lungs.

Drugs 2008; 68 (12): 1741-1770

 Summary: Properties of ciclesonide

Deposition across Large Negligible Systemic Negligible

& Small airways Effects Oropharyngeal Effects

High lung deposition • Low oral bioavailability Low oropharyngeal

• Inhalation of extra fine (<1%) deposition
formulation of ciclesonide • High systemic clearance • It is inhaled in an inactive
results in high (>50%) of des-ciclesonide form
pulmonary deposition,
• High plasma protein • Extra fine formulations
especially in the
binding (99%) leads to low
peripheral regions of the
oropharyngeal deposition
lung.

Drugs 2008; 68 (12): 1741-1770

EFFICAC
Y
 2.5 400
2.3 *
2.25
361.66**
2.25 2.18 352.28*
2.01 350 336.4
FEV1 (L)

PEFR n(L/min)
2
307.6

1.75 300

1.5
Baseline Week 1 Week 3 Week 6 250
Baseline Week 1 Week 3 Week 6
*p<0.05 compared to baseline
*p<0.05, **p<0.01 compared to baseline

• Ciclesonide is efficacious as there was significant improvement in lung function from baseline to week 6 (PEFR and FEV1)

• There was a significant improvement in the symptom scores and use of rescue salbutamol after 1 week of treatment

• Ciclesonide is safe as there were no significant differences in the urinary cortisol levels from baseline to 6 weeks.
 Both ciclesonide and fluticasone propionate significantly improved forced
expiratory volume in 1 s, forced vital capacity, and morning peak
expiratory flow (PEF) compared with baseline.
 Improved Adherence with Ciclesonide than budesonide
Ciclesonide ensures improved adherence (%
patients) p=0.03

76%

Ciclesonide group

59%

Ciclesonide group
budesonide

• Improvements in symptom score, rescue medication use and lung function with once-daily dosing of ciclesonide versus
twice-daily dosing of fluticasone propionate at similar daily doses.

• Drug adherence was significantly higher in the ciclesonide group than in the budesonide group
 Therefore, advantages of Ciclesonide
Safest steroid

• Activated in the lungs

• Low oropharyngeal deposition

• Low oral bioavailbility

• High plasma protein binding

• High systemic clearance

• No adverse effect on HPA axis with high doses

Deposit in both large and small airways

• Extra fine solution formulation

• High lung deposition

Convenience of Once Daily dosing

• High lipophilicity

• Lipid conjugation
Patient Profiles
Uncontrolled asthmatic patient on medium to high doses of
inhaled corticosteroid
• Mrs Shruti is a 45- year-old engineer with a history of persistent asthma for the last 35yrs.
• She experiences day-time symptoms more than 4 times in a week and has night-time symptoms at
least twice a month
• She has consistently been on medium to high dose of regular ICS-LABA maintenance therapy and
her doctor recommended her to take additional doses of ICS to achieve better asthma control
• She is concerned about the side effects of high doses of ICS

PATIENT’S
NEED
Mrs. Shruti needs an ICS which deposits throughout the bronchial tree and has a high
therapeutic index, as she is consistently on high doses of ICS.
 Elderly high-risk COPD patient with comorbidities

• Mr. Agarwal is a 65-year-old retired banker with a history of COPD. He has been
hospitalized twice with COPD exacerbations in the last 12 months
• He gets breathless while walking and has limited scope for daily activities
• He is a diabetic and therefore has compromised immunity which puts him at a high risk of
experiencing side effects with slow recovery
• He has currently been prescribed ICS+LAMA+LABA for COPD

PATIENT’S
NEED
Mr Agarwal needs an ICS which has a very high safety profile with negligible oropharyngeal &
systemic side effects.
 Asthmatic patient with a risk of side effects

• Ms Snehal is a 20-year old aspiring singer. She has partly controlled asthma with occasional
symptoms since the last 15yrs and uses an SOS medication frequently to relieve her symptoms
• Owing to the long-term usage of ICS, she has been experiencing hoarseness of voice in the past
6 months.
• She is worried about the side effects of her medication, and is concerned about her career as a
singer

PATIENT’S
NEED
Ms Snehal needs an ICS with optimum efficacy and minimal side effects of dysphonia therefore, an
ideal ICS with minimal oral bioavailability & oropharyngeal deposition
Severe Asthamtics with poor asthma control

• Mr Raghav is a 35- year-old chartered accountant with a history of severe persistent asthma for the last
20years
• He has night-time symptoms more than twice a month and have a history of 3 exacerbations in the last 1 year
• He has been taking medium-high doses of conventional formulations and yet, his asthma is poorly controlled.

PATIENT’S
NEED
Mr Raghav needs an ICS formulation that would improve his asthma control. Switching
from conventional formulations to extra fine formulation of ICS has shown to improve
asthma control in severe asthmatics and frequent exacerbators
 Asthmatic patient with poor adherence

• Mr Sood is a 28 yrs old cricket player with a history of controlled mild asthma
and infrequent symptoms
• He has been on daily low dose ICS for the past 12yrs.
• Owing to his long hours of practice and busy schedule, he is unable to adhere to
his twice daily asthma medication regularly

PATIENT’S
NEED
Mr. Sood needs a regular controller medication which is easier to adhere to,
preferably with once daily dosage.
 Place in Therapy

• Ciclohale Inhaler is indicated in patients >18yrs of age with persistent asthma, wherever the need
for inhaled corticosteroids has been established.
• The extra fine ciclesonide formulation targets peripheral airways inflammation and therefore, can
be beneficial for targeting patients with significant small airways disease.
• Ciclohale Inhaler might be useful in patients who need additional high doses of inhaled
corticosteroid beyond the nominal dose of ICS-LABA.
• While stepping down a patient from high doses of Budesonide and fluticasone, the patient can be
put on comparable doses of ciclesonide.
• Patients suffering from refractory eosinophilic asthma who are on high doses of steroid.
• Patients suffering from dysphonia as an adverse effect from other inhalers might find Ciclohale
Inhaler beneficial, as it has minimal oropharyngeal deposition owing to its extra fine formulation.
• Patients with an increased risk of adverse effects with ICS can be put on Ciclohale Inhaler as
ciclesonide has an excellent safety profile.
120 dosage
Pricing details:
Ciclohale MRP
80 Rs. 300
160 Rs. 325