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Tuloplast (Tulobuterol Patch-0.5/1/2 mg)

The First Transdermal Bronchodilator

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CONTENTS

Preface

Executive Summary

Asthma: Indian Perspective

COPD: Indian Perspective

Management of Asthma & COPD

Limitations of Inhaled Therapy

Transdermal Drug Delivery System

Rationale for the Tulobuterol patch formulation

Mechanism of action

Pharmacokinetics

Dosage and administration

Clinical efficacy

Clinical effects of tulobuterol patch in adults with

bronchial asthma

Clinical effects of the tulobuterol patch in children with

bronchial asthma

Tulobuterol patch vs. Slow-release theophylline (SRT)

The BAREC study: comparison between the tulobuterol

patch and inhaled salmeterol

The BAREC II study: add-on effects of the tulobuterol

patch in patients who were treated with inhaled

tiotropium

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Treatment adherence

Safety

Desensitization/Tolerance

Pharmacological Studies Supporting the Clinical Efficacy

Results

Role as a therapeutic agent for COPD

References

Clinical trial summary

Tuloplast Pack Insert

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Abbreviations

COPD: Chronic Obstructive Pulmonary Disease

DALY: Disability Adjusted Life-Years

GINA: Global Initiative Against Asthma

GOLD: Global Initiative for Chronic Obstructive Pulmonary Disease

CAT: COPD Assessment Test

mMRC: modified Medical Research Council

CFC: ChloroFluoroCarbons

TDDS: Transdermal Drug Delivery System

LABA: Long Acting Beta-2 Agonist

SABA: Short Acting beta-2 Agonist

LAMA: Long Acting Muscarinic Antagonist

ICS: Inhalational Corticosteroids

SRT: Slow release Theophylline

SGRQ: St. George Respiratory Questionnaire

HRQoL: Health Related Quality of Life

LTRA: Leukotriene receptor Antagonist

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Preface

The tulobuterol patch was developed in Japan, and is the first bronchodilator available as an

adhesive transdermal patch containing a β2-adrenergic agonist. The patch was designed for use

as chronotherapy for nocturnal asthma when applied at bedtime, and is currently used in the long-

term management of asthma and COPD in Japan, Korea, and China. The patch is applied to the

skin once daily, continuously releases its active ingredient, and maintains effective serum

tulobuterol concentrations for 24 hours.

Therefore, the tulobuterol patch provides long-acting β-agonist activity, despite tulobuterol being

categorized pharmacokinetically as a short-acting β2-agonist. Because the tulobuterol patch

requires only once-daily application, treatment adherence is excellent. Further, its clinical efficacy

and safety in the treatment of chronic airways disease have been established since its launch in

1998.

This monograph, dedicated to tulobuterol patch, presents an up to date compilation of its various

characteristic features & the comparative scientific data with conventional therapies in the

management of asthma and COPD. We also discussed the safety and patient acceptability of the

patch.

Dr. Sanjaykumar Navale;

M.B.B.S., M.D

Sr. Manager, Medical Services

Zuventus Healthcare Ltd.

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Executive Summary

1. Tulobuterol is the world's first bronchodilator drug to be available as long-acting transdermal

bronchodilator.

2. Tuloplast is a unique transdermal delivery system prepared using drug matrix technology, achieves

continuous release of tulobuterol for 24 hours after the patch is applied to the skin.

3. Serum tulobuterol levels increases gradually and then remain at steady levels.

4. Tuloplast significantly contribute to the pharmacotherapy of asthma by countering the morning dip in

respiratory function.

5. Several clinical trials confirm the efficacy of the Tuloplast in patients with asthma and COPD.

6. Evidence indicates that the drug reaches the peripheral airways via the systemic circulation, is useful

for the long-term management of COPD, and improves the patients' Quality of life (QOL).

7. The safety of the tulobuterol patch when used in otherwise healthy adults, children with asthma, and

adult patients with asthma or COPD has been well established.

8. It is notable that adherence with treatment is far better in patients using the tulobuterol patch than in

those on inhaled drugs.

9. Only once-daily application makes it useful for long-term management of chronic respiratory disease.

10. Tuloplast might become a first choice in treatment, especially for children and elderly patients who

are unable to inhale drugs reliably.

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Asthma: Indian Perspective[1]

India has an estimated 15-20 million asthmatics.

In India, rough estimates indicate a prevalence of between 10 - 15% in 5-11 year old children.

Asthma statistics in India (WHO, 2004)

57.5 estimated total deaths (‘000)

5.1 estimated deaths per 100000 populations

277 DALYs (disability adjusted life-year) per 100,000

6.5 age-standardized deaths per 100,000

268 age-standardized DALYs per 100,000

Constitutes 0.2% of all deaths and 0.5% of National Burden of Diseases (Smith 2002)

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Asthma prevalence according to National Family Health Survey-3, 2005-06

According to the recently conducted cross sectional nationally representative National Family

Health Survey (NFHS)-3, the overall prevalence of asthma among adult men and women in India

is similar with 1,696 and 1,627 per 100,000 respectively (IIPS and Macro International 2007).

The number of men and women with asthma increases steadily with age. Prevalence of asthma is

higher in rural areas (1,719 per 100,000 for women and 1,799 per 100,000 for men) than for urban

areas and that it is more common among women than men.

Asthma among men is more prevalent in the lower wealth quintiles than among the higher wealth

quintiles Moreover, prevalence is highest among those with less than five years of schooling

(2,283 per 100,000 among women and 2,640 among men per 100,000), and among those with no

education (1,914 among women per 100,000 and 2,440 among men per 100,000).

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COPD: Indian Perspective [2]

Like everywhere else in the world and especially in the developing world; India is

changing - not only in terms of its demographics, urbanization, economic profile, pollution

but also in terms of its health burden, disease pattern, dominant-disease-composition,

morbidity and mortality determinants.

India contributes a significant and growing percentage of COPD mortality estimated to be

amongst the highest in the world; i.e. more than 64.7 estimated age standardized death rate

per 100,000 amongst both sexes as shown in Figure as mentioned in the WHO Global

Infobase Updated on 20th January 2011 (India 102.3/100,000). This would translate into

approximately 556,000 in case of India (>20%) out of a world total of 2,748,000 annually.

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COPD is surpassing Malaria, TB even today and the gap would get wider with time in near

future. Since most inhalational drugs are available in the country there is no reason why

mortality should not be comparable to rest of the world but there is poor adherence to

treatment guidelines, both national and international.

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Estimated number of patients of chronic COPD 1996- 2016

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Management of Asthma[3]

The Stepwise management of Asthma in adult population according to updated GINA guidelines

2015 is as depicted in the following figure:

For children 6–11 years, theophylline is not recommended, and the preferred Step 3 treatment is medium dose ICS

Figure 3: Stepwise approach to long-term management of asthma in adults, adolescents and

children 6-11 years

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Management of COPD[4]

The division of COPD patients into four groups is as follows according to upadted GOLD

guidelines 2015:

Patient group Criteria

A CAT < 10, mMRC 0-1, 0-1 risk of exacerbations not leading to hospital admissions,

low risk according to GOLD classification of airflow limitation

B CAT ≥ 10, mMRC ≥ 2, 0-1 risk of exacerbations not leading to hospital admissions,

low risk according to GOLD classification of airflow limitation

C CAT < 10, mMRC 0-1, ≥ 1 or ≥ 2 risk of exacerbations leading to hospital admissions,

High risk according to GOLD classification of airflow limitation

D CAT ≥ 10, mMRC ≥ 2, ≥ 1 or ≥ 2 risk of exacerbations leading to hospital admissions,

High risk according to GOLD classification of airflow limitation

CAT: COPD Asssessment Test

mMRC: Modified Medical Research Council Questionnaire for Assessing the Severity of Breathlessness

The initial pharmacological Management of COPD is summarized below:

Patient Group Recommended First Choice Drug

A Short-acting anticholinergic or Short-acting beta2-agonist SOS

B Long-acting anticholinergic or Long-acting beta2-agonist

C Inhaled corticosteroid + long-acting beta2-agonist or Long-acting

anticholinergic

D Inhaled corticosteroid + long-acting beta2-agonist and/or Long-acting

anticholinergic

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Limitations of Inhaled Therapy[5]

metered dose inhaler Coordination of breathing and actuation needed

Device actuation required

High pharyngeal deposition

Upper limit to unit dose content

Remaining doses difficult to determine

Potential for abuse

Not all medications available

Many use CFC propellants in USA

Holding chamber or spacer Inhalation can be more complex for some patients

Can reduce dose available if not used properly

More expensive than MDI alone

Less portable than MDI alone

Dry powder inhaler Requires moderate to high inspiratory flow

Some units are single dose

Can result in high pharyngeal deposition

Not all medications available

Transdermal Drug Delivery System (TDDS) [6]

Transdermal drug delivery system is the topically administered medications in the form of patches

which when applied to the skin deliver the drug, through the skin at a predetermined and controlled

rate.

Controlled drug release can be achieved by transdermal drug delivery systems (TDDS) which can

deliver the drug via the skin portal to systemic circulation at a predetermined rate over a prolonged

period of time. For effective Transdermal drug delivery system, the drug should able to penetrate

the skin easily and reach the target site. TDDS increase the patient compliance and reduces the

load as compared to oral route.

Transdermal formulation maintain drug concentration within the therapeutic window for prolong

period of time ensuring that drug levels neither fall below the minimum effective concentration nor

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exceed the maximum effective concentration.

Advantages of TDDS

Avoidance of first pass metabolism of drugs.

Transdermal medication delivers a steady infusion of a drug over a prolonged period of

time. Maintains stable or constant and controlled blood levels for longer period of time.

Adverse effects or therapeutic failures frequently associated with intermittent dosing are

avoided.

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Comfort via non-invasive, painless and simple application. The simplified medication

regimen leads to improved patient compliance and inter & intra-patient variability.

It increases the therapeutic value of many drugs via avoiding specific problems associated

with the drug like GI irritation, lower absorption, decomposition due to ‘hepatic first pass’

effect.

Comparable characteristics with intravenous infusion.

This route is suitable for the administration of drugs having very short half life, narrow

therapeutic window and poor oral availability.

Flexibility of terminating the drug administration by simply removing the patch from the

skin.

Self administration is possible in these systems.

Disadvantages of TDDS

The possibility of local irritation may develop at the site of application. Problems like

Erythema, itching, and local edema can be caused by the drug, the adhesive, or other

excipients in the patch formulation.

The barrier function of the skin changes from one site to another on the same person, from

person to person and with age.

Rationale for the Tulobuterol patch formulation[7]

Nocturnal worsening of asthma (nocturnal asthma), is a common and important problem for

asthmatic patients. Nocturnal asthma is defined as variable exacerbation of the underlying asthma

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condition, which is associated with increased symptoms of airway hyper-responsiveness and/or

worsening of lung function, and a need for medication. These changes are associated with

circadian variations in lung function. Compared with the normal range of variation (5%–8%) of

lung function in healthy subjects, nocturnal asthma exaggerates the changes in pulmonary function

by >15%. This decrease in lung function in the early morning as a result of nocturnal asthma is

known as the “morning dip”.

Dethlefsen et al. investigated approximately 3000 untreated asthma patients to determine the time

of the day which asthma attacks are most frequent, and reported that the attacks occurred in

clusters at around 4:00 am. Therefore, suppression of this morning dip can be expected to bring

about an improvement in the patient's QOL and also reduce the burden on the caregiver in cases of

childhood asthma.

Chronotherapy based on the circadian rhythm is needed in asthmatics to prevent this morning dip

and to improve quality of life. The tulobuterol patch was initially developed to prevent the

morning dip and to sustain drug efficacy over 24 hours (Figure 1)

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Tulobuterol Patch was designed in accordance with the concept of chronotherapy: the blood drug

concentration is controlled in such a manner that it is the highest during early morning, when the

respiratory functions are most severely suppressed. This controlled release helps to reduce the

systemic adverse reactions associated with excessive drug concentrations in the blood. [3]

Tulobuterol patch employs a technology that prolongs the duration of the drug's action to 24 h.

This technology is the drug matrix system, which has been patented for the patch.

Figure 1 Time profiles for serum concentration of tulobuterol.

Notes: Dashed line indicates the ideal time profile of the serum concentration of tulobuterol on the

basis of circadian pulmonary function (line). When the tulobuterol patch is applied before bedtime,

the maximum concentration of tulobuterol is achieved during the morning dip (bold line).

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To accomplish this, a matrix-type transdermal delivery system was used for formulation of the

tulobuterol patch. The patch contains both crystallized and molecular forms of tulobuterol in an

adhesive layer. It also includes a controlled drug release mechanism known as the drug matrix

system (Figure 2).

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Figure 2: Drug Matrix system.

Notes: The tulobuterol patch contains crystallized (closed rhombus) and molecular (open circle)

forms of tulobuterol in an adhesive layer. When the patch is applied to the skin, molecular

tulobuterol is gradually absorbed percutaneously. During application, the number of molecules in

the patch is decreased. Subsequently, these molecules are supplied from the crystals.

After the tulobuterol patch is applied to the skin, the molecular tulobuterol is gradually

absorbed percutaneously.

As the number of tulobuterol molecules in the patch decreases, additional molecules are

supplied by dissociation of the tulobuterol crystals into a molecular and absorbable form.

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This mechanism enables timed release of tulobuterol - the drug concentration peaks when

the symptoms of asthma are at their worst.

Currently available oral β2-agonists- salbutamol, terbutaline, and bambuterol, reach peak

levels in serum within 3 hours of administration, patients with asthma who take these

medications before bedtime cannot achieve maximum bronchodilation when most needed

during the morning dip.

In addition, oral β2-agonists often have clinically significant systemic adverse effects, such

as tremor and palpitations, due to steep increases in plasma drug levels.

The tulobuterol patch provides gradual and continuous drug release, so reduces the risk of

systemic adverse effects caused by high plasma drug concentrations.

Mechanism of action [8]

Tulobuterol produces bronchodilation by directly stimulating β-2 receptors in airway smooth

muscle. Occupation of β-2 receptors by tulobuterol results in the activation of the Gs-adenylyl

cyclase-cAMP-PKA pathway, resulting in phosphorylative events leading to bronchial smooth

muscle relaxation (Figure). There is a rapid decrease in airway resistance.

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Molecular actions of β2 agonists to induce relaxation of airway smooth muscle cells. Activation of

β 2 receptors results in activation of adenylyl cyclase (AC) via a stimulatory G protein (Gs), leading

to an increase in intracellular cyclic AMP and activation of PKA. PKA phosphorylates a variety of

target substrates, resulting in opening of Ca2+

-activated K+ channels (KCa), thereby facilitating

hyperpolarization, decreased phosphoinositide (PI) hydrolysis, increased Na+/Ca

2+ exchange,

increased Na+,Ca

2+- ATPase activity, and decreased myosin light chain kinase (MLCK) activity. β2

Receptors may also couple to KCa via Gs. PDE, cyclic nucleotide phosphodiesterase.

Tulobuterol

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Pharmacokinetics[9]

Pharmacokinetic parameters during application of Tulobuterol Patch

Dose

(No. of

cases)

Drug administered Cmax

(ng/mL)

Tmax

(hr)

T1/2

(hr)

AUC0-48hr

(ng•hr/mL)

0.5 mg

[n=23]

Tulobuterol Patch 0.5 mg 0.48 ± 0.22 11.4 ± 4.1 11.1 ± 4.4 10.75 ± 7.65

Standardized preparation (adhesive skin patch 0.5 mg) 0.42 ± 0.20 15.4 ± 5.0 10.6 ± 4.2 10.67 ± 7.26

1 mg

[n=24]

Tulobuterol Patch 1 mg 0.59 ± 0.32 9.1 ± 2.1 10.4 ± 1.9 11.09 ± 6.86

Standardized preparation (adhesive skin patch 1 mg) 0.56 ± 0.27 11.5 ± 3.7 9.7 ± 1.3 12.10 ± 7.35

2 mg

[n=24]

Tulobuterol Patch 2 mg 1.29 ± 0.60 11.0 ± 2.7 11.0 ± 3.4 27.62 ± 18.77

Standardized preparation (adhesive skin patch 2 mg) 1.24 ± 0.63 14.5 ± 4.5 10.0 ± 4.5 29.65 ± 20.62

(Mean ± S.D.)

Bioequivalence Study

The concentration of Tulobuterol in plasma was measured (crossover method) after single

transdermal application (chest, 24 hours) of Tulobuterol Patch 0.5 mg, 1 mg and 2 mg and

standardized preparation corresponding to each standard to healthy adult males, and the statistical

analysis of pharmacokinetic parameters (AUC, Cmax) confirmed bioequivalence for both drugs.

(The usual dose in adults is 2 mg per dose as Tulobuterol.)

The plasma concentration-time graph of tulobuterol patch against standardized preparation is

depicted below.

TULOBUTEROL PATCH 2 mg Standardized preparation (adhesive skin patch 2 mg) Mean ±SD (n=24) Mean±SD (n=24)

Time after application (hr)

Detachment

Pla

sma

con

cen

trat

ion o

f T

UL

OB

UT

ER

OL

(n

g/m

L)

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Pharmacokinetics of Tulobuterol Patch in healthy male volunteers[10]

When the 2 mg tulobuterol patch was administered, it was well absorbed, with an

absorption lag-time of about four hours.

Serum tulobuterol concentrations peaked at 9–12 hours and decreased gradually over the

24 hours. The maximum serum tulobuterol level was 1.4 ng/ml, which is higher than the

target effective serum concentration of 1.0 ng/ml.

The serum tulobuterol level was maintained in an effective range for a longer period after

application of the patch.

The mean % of drug absorbed during the application of a patch for 24 h was 82-90% after a

single dose and 82-85% during repeated dosing.

Mean urinary recovery of unchanged drug after application was 6%.

According to the literature, the tulobuterol patch is suitable for preventing the morning dip

because peak serum drug levels are achieved during the early morning.

Pharmacokinetics the tulobuterol patch in childhood asthma [11]

Similar pharmacokinetics was observed when used in children with asthma.

When subjects weighing, < 30 kg received a 1 mg tulobuterol patch and those weighing ≥ 30 kg

received the 2 mg tulobuterol patch, the serum concentration of tulobuterol peaked 12 hours after

application and remained at appropriate levels for 24 hours after application.

The peak plasma tulobuterol level was 1.33 ng/ml and the time taken to reach this level was 14

hours.

PEF was significantly improved after application of the tulobuterol patch and no side effects were

reported.

Therefore, the tulobuterol patch is also suitable for use in children with asthma.

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DOSAGE AND ADMINISTRATION [7]

Once daily, apply the patch to chest, back, or upper arm as per the following dosage regimen.

• For children aged 6 months to 3 years: 0.5 mg

• For children aged 3 to 9 years: 1.0 mg

• For adults and children aged > 9 years: 2.0 mg

Although the timing of application for the tulobuterol patch is not clearly described and may

depend on disease status, it will be most effective for treatment of asthma if applied in the evening

or at bedtime.

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Therapeutic Classification of anti asthma drugs [12]

CLASSIFICATION MEDICATION DRUGS

CONTROLLERS 1. Taken daily on a long-term basis

2. Prophylactic and preventive medication

1. Inhaled corticosteroids

2. Long-acting bronchodilators

3. Anti-allergic agents

[Leukotriene inhibitor,

Thromboxane A2 inhibitor, Th2

cytokine inhibitor, Mast cell

stabilizer, etc]

RELIEVERS 1. Taken on demand

2. Quick relief for the severe symptoms

1. Rapid-acting inhaled β2-

agonists

2. Systemic glucocorticoids

3. Anti-cholinergics

4. Methylxanthines

CLINICAL

Efficacy

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CLASSIFICATION AS LONG-ACTING BETA AGONISTS (LABA) [12,13,14]

Tulobuterol patch is a unique β2 agonist drug preparation that allows transdermal delivery

of tulobuterol through the drug matrix system, thereby avoiding the decrease in respiratory

functions during the early morning hours (morning dip) seen in asthma patients receiving

other formulations. This is because the patch prevents excessive increase in blood drug

concentrations, while also reducing the incidence of systemic adverse reactions.

The effect of the drug after once-daily application persists for over 24 h, and the

formulation is designed such that, once the patch is applied at bedtime, the blood drug

concentration reaches its peak in the early morning and the therapeutic effect is sustained

for a prolonged period.

The tulobuterol patch was found to exert an additive effect when combined with ICS in

bronchial asthma patients therefore; the patch is positioned as a LABA in the Japanese

Guidelines for Prevention and Management of Asthma and in the Guidelines for Diagnosis

and Treatment of COPD.

The synergistic effects of ICS and LABAs are explained by the fact that inhaled steroids

increase the expression of β2 adrenergic receptors, while β

2 adrenergic agonists causes the

down regulation of these receptors. On the other hand, the β2 agonists activate the steroid

receptors to potentiate the effect of the steroids. In addition, the tulobuterol patch may exert

both local effects on the lungs and systemic effects.

Yamaguchi et al. investigated the effect of tulobuterol on the adhesive forces between

blood eosinophils and human umbilical vein endothelial cells (HUVEC) in an in

vitro study. They reported that tulobuterol significantly inhibited the adhesion between

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eosinophils and HUVECs activated by IL-4 + TNFα, IL-5, or formyl-methionyl-leucyl-

phenylalanine. Thus, tulobuterol can decrease the adhesion of blood eosinophils to

endothelial cells.

These findings imply that the tulobuterol patch may possibly exert an anti-inflammatory effect.

ICS are the most effective controllers and are the first-choice anti-inflammatory therapy for

asthma. In the Japanese guideline for prevention and management of asthma, and GOLD

guidelines the tulobuterol patch is also categorized as a controller medication.

Although ICS are widely used as first-line controllers in the long-term management of

asthma, ICS alone are insufficient when treating patients with moderate to severe asthma.

Such patients frequently experience the morning dip.

In the Global Initiative for Asthma, a global guideline for the treatment of asthma, LABAs

are positioned as the first add-on controllers for ICS because they can significantly improve

airflow obstruction and symptoms.

Use of LABAs as monotherapy is not recommended because these medications have no

effects on airways inflammation in asthma and could mask underlying inflammation.

Therefore, LABAs should be used only in combination with ICS for the management of

asthma.

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CLINICAL EFFECTS OF TULOBUTEROL PATCH IN ADULTS WITH BRONCHIAL ASTHMA [3]

According to the GINA & Japanese Guideline for Prevention and Management of Asthma, inhaled

corticosteroids (ICS) are the first choice of drugs for the long-term management of bronchial

asthma. β 2-agonists are the strongest bronchodilators among the standard drugs used to treat

bronchial asthma. The combination of ICS and a long-acting β2-agonist (LABA) is therefore

recommended for the management of asthma from Step 2 onward.

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CLINICAL EFFECTS OF THE TULOBUTEROL PATCH IN CHILDREN WITH

BRONCHIAL ASTHMA [15]

Studies show that the combined use of the tulobuterol patch and an ICS is effective in the

treatment of bronchial asthma in children. In addition, the tulobuterol patch has the advantage of

being highly convenient to use in children of all ages.

Yoshihara et al. conducted a randomized, parallel-group, comparative study in 10 pediatric

patients with severe asthma who were under ICS treatment. Once-daily application of tulobuterol

patch showed an add-on effect equivalent to that of inhaled salmeterol (twice-daily inhalation). In

addition, comparison of increasing the dose of the ICS vs. adding the tulobuterol patch to the ICS

in 18 pediatric patients with severe asthma showed that combination of ICS plus Tulobuterol patch

resulted in a significantly greater improvement in the PEF values and a significantly higher

percentage of respiratory symptom-free days than increasing the ICS dose.

These results show that the tulobuterol patch is also useful for the long-term management of

asthma in the pediatric population. Thus, the tulobuterol patch appears to be suitable for the

treatment of asthma in almost all age groups, from infants aged ≥6 months to the elderly, and the

combined application of this patch with an ICS plays an important role in the long-term

management of asthma.

Positioning In Asthma[3,16,17]

Combination of ICS and a long-acting β2-agonist (LABA) is therefore recommended

for the management of asthma from Step 3 in adults, adolescents and children between

age 6-11 years

ICS-LABA as initial controller therapy:

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a. Low dose ICS-LABA combination is recommended as initial controller therapy if

there are troublesome asthma symptoms most days; or waking due to asthma once a

week or more especially if any risk factors exist (Evidence A)

b. Moderate dose ICS-LABA is recommended as initial controller therapy if initial

asthma presentation is with severely uncontrolled asthma or with acute exacerbation

(Evidence D)

In the Japanese guidelines for childhood asthma 2014, the tulobuterol patch is classified as

LABA which is recommended to be used from Step 3.

The International Consensus on Pediatric Asthma 2012 published in European Journal of

Allergy and Clinical immunology recommends the use of LABA from Step 2 onwards.

TULOBUTEROL PATCH vs. SLOW-RELEASE THEOPHYLLINE (SRT) [18]

Minami et al. conducted a randomized controlled study of the tulobuterol patch and SRT in 16

patients with moderate to severe COPD. A significantly greater improvement in subjective

symptoms and the QOL in the tulobuterol patch group than in the SRT group. Evaluation of the

number of expectorations, ability to expectorate, wheezing score, cough score, and the

"Total," "Impact," and "Symptoms" scores in the SGRQ revealed a significantly greater

improvement in the tulobuterol patch group than in the SRT group. The only adverse reaction

noted was increased volume of sputum in one case in the tulobuterol patch group.

Kanehara et al. compared theophylline and tulobuterol in 26 patients with mild to moderate

COPD, by using a crossover design. These authors reported that, while only patients treated with

theophylline showed improvement in respiratory functions, an anti-inflammatory effect on

neutrophil inflammation was not observed with either drug. However, six patients treated with

theophylline—five of whom developed adverse reactions and one who cited personal reasons—

dropped out of the study, while all patients treated with tulobuterol completed the study. Thus,

clinical evaluation of this study may be difficult.

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THE BAREC STUDY: COMPARISON BETWEEN THE TULOBUTEROL

PATCH AND INHALED SALMETEROL [19]

Fukuchi et al. conducted a multicenter, parallel-group, comparative study (the BAREC study) of

the tulobuterol patch and inhaled salmeterol in 92 patients with stable COPD (GOLD stage II and

III phases). They reported improvements in the morning and evening PEF values in both groups,

with no significant intergroup difference (Fig.).

Improvement in the morning (A: left panel) and evening (B: right panel) PEF values over a 12-week treatment

period with tulobuterol patch and inhaled salmeterol in patients with stable COPD.

However, a significantly greater improvement of the SGRQ at 8 weeks after the start of treatment

was observed in the tulobuterol patch group compared with the salmeterol group (Fig.).

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In addition, treatment compliance was also significantly better in the tulobuterol patch group than

in the salmeterol group. No serious adverse reactions occurred in either group. These findings

show that, in terms of clinical efficacy, the tulobuterol patch is equivalent or superior to inhaled

salmeterol and that it is useful in the long-term management of patients with stable COPD.

Yamagata et al. conducted a crossover comparative study of salmeterol and tulobuterol in 11

COPD patients. Their study revealed that the forced expiratory volume in 1 second (FEV1) and

forced vital capacity (FVC) were significantly higher in the salmeterol group than in the

tulobuterol group. However, because the sustained-release technology in tulobuterol is designed

such that the drug is effective for 24 h, a steady concentration of the drug is achieved after the

patch has been applied two or more times, therefore, the effect of a single dose may not have been

100%. On the other hand, we speculate that a sufficient effect of salmeterol might have been

obtained 24 h later because the second dose had been administered within this period.

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THE BAREC II STUDY: ADD-ON EFFECTS OF THE TULOBUTEROL PATCH IN

PATIENTS WHO WERE TREATED WITH INHALED TIOTROPIUM [20]

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Japanese Guidelines

recommend combining 2 or more drugs rather than increasing the dose of a single drug when a

single drug fails to sufficiently alleviate the symptoms. This is because the use of multiple drugs

with differing mechanisms of action has shown better treatment outcomes in COPD, without an

increase in the frequency of adverse reactions. Ichinose et al. conducted a multicenter, parallel-

group comparative study (the BAREC II study) to evaluate the clinical effects and safety of a

combination of the tulobuterol patch and inhaled tiotropium in patients with COPD.

Effect of using the tulobuterol patch in combination therapy on morning (A: left panel) and evening (B: right panel) PEF

values. *p < 0.05, **p < 0.01

After a 2-week run-in period, 103 patients with stable COPD were randomized to receive either

inhaled tiotropium alone (Tio group) or both tulobuterol patch and inhaled tiotropium (Tio + Tulo

group). In both groups, the FVC and FEV1 as well as the dyspnea improved significantly after 8

weeks of treatment. A comparison of both groups showed that the percent changes in the

Tuloplast monograph

inspiratory capacity and morning and evening PEF values were significantly greater in the Tio +

Tulo group than in the Tio group.

Effect of tulobuterol patch used in combination therapy on St George’s Respiratory Questionnaire. *p < 0.05,

***p < 0.001, †p < 0.05 (Intergroup)

In addition, a significant improvement in the total SGRQ score and improvements in the "Activity"

and "Impact" scores were observed only in the Tio + Tulo group. Adverse reactions suspected to

be causally related to the treatment included mild urticaria and decreased mastication in one case

in each groups; moderate dysuria associated with elevated blood pressure in one case in the Tio

group; and mild headache in one case of the Tio + Tulo group. In COPD patients, addition of the

tulobuterol patch to inhaled tiotropium produced significant improvements in dyspnea and SGRQ

score, as well as in the pulmonary function parameters. These benefits may be attributable to a

reduction in pulmonary hyperinflation resulting from an improvement in the patency of the

peripheral airways affected by tulobuterol entering the systemic circulation. Akamatsu et

al. divided 60 COPD patients into two groups—one treated with tulobuterol alone or the other

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treated with a combination of tulobuterol and tiotropium—and assess their respiratory functions.

The findings of this study supported those of the BAREC II study, confirming the add-on effects of

tulobuterol when combined with tiotropium.

TREATMENT ADHERENCE [21]

Treatment adherence is very important in the management of patients with chronic respiratory

diseases. Treatment adherence - The % of patients who took the prescribed drug as instructed.

a) Although inhaled drugs play central roles in the treatment of chronic respiratory diseases,

such as asthma and COPD, they are often associated with low treatment adherence.

Preferred frequency of administration

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b) Tamura and Ohta conducted a web-based survey (n=1470) on the treatment adherence to

drugs used in asthma and COPD patients. Treatment adherence was significantly higher to

the tulobuterol patch (84 %) than that for any inhaled drug (31 to 64.6%).

The complexity of the inhalation technique, difficulty in mastering the technique for

using inhalers and insufficient inhalation rate

The need for frequent administration of an inhaled drug

These are the reasons for the lower treatment adherence to inhaled drugs.

c) Further, the % of individuals who preferred once-daily administration was 83.2%.

d) Patient adherence to the use of the tulobuterol patch is high because of the ease of its

application and the need for only once-daily administration. The patch satisfies the

prerequisites of a drug for long-term management of chronic respiratory diseases, such as

asthma and COPD.

e) Sugawara et al. compared the treatment adherence of salmeterol to that of tulobuterol in 26

patients with moderate to severe COPD using a crossover design. Among patients aged <80

y, adherence to tulobuterol was found to be better than that to salmeterol, and a similar but

more significant difference was noted among those aged ≥80 y. The findings of this study

support the results reported by Tamura and Ohta.

Safety

1. Tulobuterol released from the patch did not accumulate during repeated transdermal

application in healthy adults.

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2. It was well tolerated, except for an increase in heart rate of 10–20 beats/min after 5

consecutive applications of a 4 mg patch.

3. No signs of tachyphylaxis after use for a year in adult patients.

4. No serious adverse events have been reported in patients with asthma, childhood asthma or

COPD.

5. Mild adverse events reported as follows: itching, eruption, contact dermatitis, tremor,

palpitation, numbness, increased serum creatinine phosphokinase, & abnormal hepatic

function. These side effects resolved after stopping the patch.

6. Skin problems can be reduced by not applying the patch repeatedly to the same body site.

Desensitization/Tolerance [22]

In the treatment of chronic respiratory diseases, it is important that long-term use of a drug is not

associated with reduced efficacy; that is, that no tolerance is induced by its long-term use.

Concern related to the use of the tulobuterol patch is that continuous and repeated exposure to β-

agonists leads to reduced relaxation of smooth muscle in the airways, referred to as desensitization

to β-adrenoceptor agonists. However, Kume et al have reported that chronic exposure to low

concentrations of tulobuterol does not lead to desensitization of β-adrenoceptors on smooth muscle

cells in the airways.

Neither a decrease in efficacy nor the development of tolerance was observed with the use of the

tulobuterol patch, even after year-long use. Therefore; the tulobuterol patch is well tolerated and

can be used for the long-term management of asthma and COPD in any age group.

Tuloplast monograph

Pharmacological Studies Supporting the Clinical Efficacy Results

Promotes airway ciliary movement [23]

Study demonstrated that tulobuterol promotes airway ciliary movement, thereby enhancing airway

clearance. This effect may underlie the improvement of expectoration and cough, which are the

subjective symptoms of COPD. COPD patients have low flat diaphragms, and the consequent

decrease in the contractility of the respiratory muscles may be associated with decreased

respiratory functions and subjective symptoms in patients with COPD.

Improves Diaphragm muscle contractility [24]

Shindoh et al. found that the increased contractility of the diaphragmatic muscle was maintained

for 24 h after the application of the tulobuterol patch and that the patch suppressed the decrease in

the contractility of the diaphragmatic muscle for 24 h. These findings suggest that the tulobuterol

patch may increase the contractility of the weakened diaphragmatic muscle in both asthma and

COPD patients.

Does not affect night sleep [25]

Burioka et al. assessed the effects of tulobuterol on the expression of the human clock

gene Per1 mRNA and confirmed that the drug does not affect its expression. This finding implies

that the administration of tulobuterol at bedtime does not affect night sleep.

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ROLE AS A THERAPEUTIC AGENT FOR COPD [4] (Updated GOLD 2015. Available from

URL: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015_Apr2.pdf)

Tulobuterol in stable COPD

1. Bronchodilators are central to symptoms of management in COPD.Bronchodilators are

prescribed on as needed or on a regular basis to prevent or reduce the symptoms

2. Long-acting formulations of beta2-agonists (LABA) are preferred over short-acting

formulations. Because they are convenient and more effective at producing stable

symptom relief than short acting bronchodilators.

3. Long-term treatment with inhaled corticosteroids added to long-acting bronchodilators is

recommended for patients with high risk of exacerbations.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) updated on

Jan 2014.

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GOLD-2014 guideline recommends Tulobuterol 2 mg transdermal patch under

long acting β2 agonist with duration of action for 24 hour (once daily) which is

unmatched by other beta2-agonists (except Indacaterol).9

a) Treatment of COPD has been focused not only on improving respiratory functions but also

on the patients' QOL. Early aggressive treatment, including the use of LABA, can improve

the prognosis of the disease.

b) In particular, because many COPD patients are elderly and have problems such as

difficulty mastering the technique of using inhalers and insufficient inhalation rates, a

different, more convenient route of administration may be useful for these patients.

c) In the BAREC study,10

once-daily transdermal tulobuterol is as effective as or better than

the inhaled salmeterol in the management of stable COPD, with significant effects on

quality of life probably by relieving the peripheral airway obstruction. Use of the

tulobuterol patch causes the drug to reach the peripheral airways through the systemic

circulation after transdermal absorption, thereby maintaining the patency of the peripheral

airways and resulting in more effective expiration and reduction of the residual volume.

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d) This prevents pulmonary hyperinflation and improves the exercise tolerance, which in turn

improves the patients' QOL.

e) Pathologically, COPD involves mainly the peripheral airways. Thus, the improvement in

peripheral airway function may well be the reason for the improvement in QOL brought

about by the use of the tulobuterol patch.

f) In the BAREC II study, 11

an add-on effect of the tulobuterol patch was noted in patients

treated with inhaled tiotropium and the difference sites of action of these two drugs was

speculated to underlie this effect: tiotropium exerts its effects via muscarinic M3 receptors,

while tulobuterol acts via the β2 adrenergic receptors. Because activated muscarinic M3

receptors are found mainly in the central airways,

g) Tiotropium, an anticholinergic agent, may mainly improve the functions of the central

airways rather than those of the peripheral airways. On the other hand, tulobuterol may

activate the β2adrenergic receptors in the peripheral airways via the systemic circulation;

thus, the combination of the two agents has complementary effects and improves the

functions of both the peripheral and central airways.

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Comparison of Tulobuterol Patch with other inhaled and oral Beta2 Agonist and SRT

Drug

Heading

Tuloplast

(Tulobuterol

Trasndermal

Patch)

Inhaled

Salmeterol

Inhaled

Formoterol

Oral Salbutamol Oral

Levosalbutamol

Oral Slow Release

Theophylline(SRT)

Category LABA LABA LABA SABA SABA Long acting

Bronchodilator

Half life (hours) 0.5 mg: 7-15

1 mg: 8-12

2 mg: 7-15

5.5 10 5 3-9 hours

Pediatric

population

Approved for all

except in children <

6 months of age

Not approved

for children < 4

years of age

Not approved for

children < 6 years

of age

Not approved for

children < 2 years

of age

Not approved for

children < 6 years

of age

Not approved for

children <2 years of

age

Geriatric

population

Can be used but to

start with a lower

dose

No difference

in efficacy and

safety with

younger

population

No difference in

efficacy and

safety with

younger

population

Can be used but

to start with a

lower dose

Careful attention to

dose reduction and

frequent serum

monitoring needed

Adverse Effects Significantly lower

risk compared to

oral tablet

Tremors; 0.9%

Palpitation: 2.6%

Tremors,

palpitations and

tachycardia

common

Tremors,

palpitations and

tachycardia

common

Tremors: 10-20%

Anxiety: 9-20%

Headache,

tachycardia,

palpitations

Palpitations,

tremors,

tachycardia,

headache

common but lesser

compared to

salbutamol

Nausea, gastric

irritation, palpitations,

tachycardia,

arrhythmias,

convulsions,

headache, CNS

stimulation

Adherence

(Tamura G et al)

84% 53-64%

Convenience Asthma: 79.3%

very easy

COPD: 73.2% very

easy

Asthma: 42.7% very easy

COPD: 32.1% very easy

Densensitization/

Tolerance

One year treatment

with Tulobuterol

TTS does not

Prone to develop tolerance

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appear to cause

tachyphylaxis

Quality of Life Improvement in

total SGRQ score

from baseline

(-4.6)

No significant improvement as

compared to Tulobuterol patch

Improvement in total

SGRQ score from

baseline

(-2.5)

Source:

Tuloplast Presribing Information

AccuNeb® Inhalation Solution. Available from: URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020949s024lbl.pdf

FORADIL AEROLIZER. Available from: URL http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020831s028lbl.pdf

SALAPIN - Salbutamol Syrup 2mg/5ml. Available from: URL. https://www.medicines.org.uk/emc/medicine/24470

Theophylline Extended Release. Available from: URL: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06ab3df7-e64a-4c46-8a70-

38561ffea5f5 Neulin SA 125 mg Tablets. Available from: URL: https://www.medicines.org.uk/emc/medicine/4862

Albuterol Sulfate tablet. Available from: URL: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c1f3881-2b68-4bdb-a12f-

8134fe8ba961

LEVOLIN Tablets/Syrup. Available from: URL http://beta.ciplamed.com/content/levolin-tabletssyrup

Tamura G, Ohta K. Adherence to treatment by patients with asthma or COPD: comparison between inhaled drugs and transdermal patch. Respir Med.

2007;101(9):1895-902

Risks of Salbutamol use. Available from: URL: http://www.ch.ic.ac.uk/local/projects/mohataren/Files/risks.htm

New Treatments for Asthma. Available from: URL: http://lrp.ersnet.org//abstract_print_07/files/226.pdf

Tuloplast monograph

Tuloplast monograph

References

1. Sutapa Agrawal. ASTHMA. South Asia Network for Chronic Disease, New Delhi.

http://sancd.org/uploads/pdf/Asthma_factsheet.pdf

2. Arvind B. Bhome. COPD in India: Iceberg or volcano? J Thorac Dis. Jun 1, 2012; 4(3): 298–

309

3. Updated GINA 2015. Available from: URL:

http://www.ginasthma.org/local/uploads/files/GINA_Report_2015.pdf

4. Updated GOLD 2015. Available from URL:

http://www.goldcopd.org/uploads/users/files/GOLD_Report_2015_Apr2.pdf

5. Device Selection and Outcomes of Aerosol Therapy: Evidence-Based Guidelines. American

College of Chest Physicians/American College of Asthma, Allergy, and Immunology

6. Ajay Sharma, Seema Saini, AC. Rana. Transdermal Drug Delivery System: A Review.

International Journal of Research in Pharmaceutical and Biomedical Sciences. Vol. 4 (1) Jan–

Mar 2013. P-286-92

7. Ichikawa T, Sugiura H. Long-term safety, efficacy, and patient acceptability of the tulobuterol

patch. April 2013 Volume 2013:2 Pages 9—18. http://dx.doi.org/10.2147/RRTD.S34031

8. Pulmonary Pharmacology. In Goodman & Gilman’s The Pharmacological Basis of

Therapeutics. Brunton LL. Chabner BA, Knollmann BC eds. USA. McGraw Hill Inc; 2011.

9. Tulobuterol patch international prescribing information. http://www.kegg.jp/medicus-

bin/japic_med?japic_code=00053366

10. Uematsu T, Nakano M, Kosuge K, Kanamaru M, Nakashima M. The pharmacokinetics of the

beta 2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation. Eur J Clin

Pharmacol. 1993;44(4):361-4.

11. Iikura Y et al. Pharmacokinetics and pharmacodynamics of the tulobuterol patch, HN-078, in

childhood asthma. Ann Allergy Asthma Immunol. 1995 Feb;74(2):147-51.

12. Ohta K et al. Japanese guideline for adult asthma. Allergol Int. 2011 Mar;60(2):115-45. doi:

10.2332/allergolint.11-RAI-0327.

13. Bames PJ. Scientific rationale for inhaled combination therapy with long-acting β2-agonists

and corticosteroids. Eur Respir J 2002; 19: 182–191

14. Yamaguchi, T., Nagata, M., Miyazawa, H. et al, Tulobuterol, a β2-agonist, attenuates

eosinophil adhesion to endothelial cells. Allergol Int. 2005;54:283–288.

15. Tamura G, Ichinose M, Fukuchi Y, Miyamoto T. Transdermal tulobuterol patch, a long-acting

(2)-agonist. Allergol Int. 2012 Jun; 61(2):219-29.

16. Hamasaki Y et al. Japanese guidelines for Childhood Asthma 2014. Allergology International

2014. 63: 235-56

17. Papadopoulos NG et al. International Consensus on Pediatric Asthma. Allergy. 2012; 67: 976-

97

18. Minami S et al. Clinical efficacy of the transdermal tulobuterol patch in patients with chronic

obstructive pulmonary disease: a comparison with slow-release theophylline. Intern Med.

2008;47(6):503-9

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19. Fukuchi Y. Clinical efficacy and safety of transdermal tulobuterol in the treatment of stable

COPD: an open-label comparison with inhaled salmeterol. Treat Respir Med. 2005; 4(6):447-5

20. Ichinose M et al. Beta-2 Agonist Research and Evaluation Committee in COPD (BAREC)

Study Group. Additive effects of transdermal tulobuterol to inhaled tiotropium in patients with

COPD. Respir Med. 2010 ;104(2):267-74

21. Tamura G, Ohta K. Adherence to treatment by patients with asthma or COPD: comparison

between inhaled drugs and transdermal patch. Respir Med. 2007;101(9):1895-902

22. Kume H. Clinical Use of 2-adrenergic Receptor Agonists Based on Their Intrinsic Efficacy.

Allergology International. 2005;54:89-97

23. Matthys H. Action of tulobuterol and fenoterol on the mucociliary clearance.

Respiration 1987; 51: 105-12

24. Shindoh C et al. Transdermal Treatment with tulobuterol Increases Isometric contractile

Properties of Diaphragm Muscle in Mice. Tohoku J Exp. 2007; 212: 309-17

25. Burioka N. Treatment with beta2-adrenoceptor agonist in vivo induces human clock gene,

Per1, mRNA expression in peripheral blood. Chronobiol Int. 2007; 24(1):183-9

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CLINICAL TRIAL SUMMARY

Adult Asthma

SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

1. Horiguchi T et al. 2004.

Inhalational steroids and tulobuterol Transdermal Thearpeutic System (TTS) OR Tulobuterol TTS without inhalational steroids

Open label 1 year 36 Mildly persistent or moderately persistent asthma

1. PEF exhibited significant improvements at 6 months and 1 year in patients treated with or without inhalational steroids.

2. One-year treatment with tulobuterol TTS did not appear to cause tachyphylaxis

3. Tulobuterol TTS significantly improves the Quality of Life of asthma patients due to: a. Significantly lower incidence of incidence of

adverse effects including palpitations and shivering as compared to oral preparations

b. Remarkable improvement of pulmonary function and symptoms of airway obstruction without increasing airway responsiveness

even after repeated use

c. Simple to use d. Better Clinical efficacy[1]

2. Kato h et al. 2002.

Tulobuterol transdermal formulation

Review Bronchial Asthma

1. Tulobuterol TTS is superior as compared to oral formulations of Beta2 agonists in terms of pharmacokinetic profile and clinical trial efficacy

2. Tulobuterol TTS is first transdermal chrono-delivery system reported anywhere in the world, and is expected to provide more effective and safe treatment of asthma and related diseases in both adults and children.[2]

3.. Su N et al. 2007.

Tulobuterol tape

Multicentre, randomized,

4 weeks 233 Mild and moderate

1. After 4 weeks of treatment, the morning peak expiratory flow (PEF) and evening PEF and the

Tuloplast monograph SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

Vs Tulobuterol tablet

Open label persistent asthma

percent change in the tulobuterol tape group were increased significantly as compared to the tulobuterol tablet group.

2. The incidence of adverse reactions including palpitations and tremor in the tulobuterol tape group was significantly lower than that in the tablet group

3. Tulobuterol tape is a newly formulated, effective and safe medication for the treatment of asthma.[3]

4. Burioka N et al. 2005.

Transdermal tulobuterol chronotherapy

Open label 6 days 13 Nocturnal Asthma

1. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h

group average PEF from 276 +/- 45 L/min to 363

+/- 67 L/min.

2. The group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy

3. Tulobuterol chronotherapy significantly increased both the level and stability of airway function over 24 hours.[4]

5. Nishiyama O et al. 2006.

Tulobuterol patch 2 mg OD VS Inhaled salmeterol 50 mg BD

Randomized, prospective, crossover

4 weeks each treatment

54 Moderate to severe asthma

1. The mean morning PEF and HRQoL score were significantly improved in both groups i.e salmeterol and tulobuterol in treatment periods as compared to run in periods

2. The tulobuterol patch may be useful as a controller medication in addition to inhaled corticosteroids in moderate to severe asthma[5]

6. Kume H et al. 2002.

Tulobuterol patch 2 mg once daily

Open label prospective

8 weeks 7 Bronchial Asthma with morning dip in PEFR inspite of use of inhaled glucocorticoi

1. The early morning reduction in PEF rate was suppressed with tulobuterol treatment and PEF values were increased from 367 +/- 35 to 439 +/- 38L/min.

2. The rescue use of inhaled beta-AR agonists was decreased from 6.9 +/- 2.0 to 1.0 +/- 0.7 puffs/week.

Tuloplast monograph SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

ds 3. Symptom scores also decreased from 8.3 +/- 3.4

to 2.1 +/- 1.4 score/week.[6] 7. Hozawa S et al.

2009. a. ICS alone Vs ICS plus Tulobuterol Patch (TP) 2 mg/day b.TP plus ICS Vs Slow release Theophylline (SRT) plus ICS Vs Leukotriene Receptor Antagonist (LTRA) plus ICS Vs ICS alone

Randomized,prospective Randomized,prospective

4 weeks 4 weeks

24

65

Asthma receiving ICS alone Asthma receiving ICS alone

1. In the TP group, improvement of bronchial hyperresponsiveness and decrease in percentage of sputum eosinophils both indicated a statistically significant difference.

2. FEV1 and PEF markedly increased after treatment with TP compared with treatment with SRT or LTRA.

3. TP can be used as a long-term add-on controller for patients with asthma receiving ICS.[7]

8. Tamura G et al. 2005.

Tulobuterol tape 1 mg vs 2 mg

randomized, double-blind, double-dummy, parallel-group, multicenteric

4 weeks 239 Asthma patients requiring inhaled short-acting β2-agonists despite treatment with inhaled corticosteroids

1. Mean morning PEF values in the 1 and 2 mg/day

groups were significantly increased from the baseline

value by 23.8 and 35.9 L/min at week 4, respectively

2. The mean evening PEF was significantly increased

in both treatment groups compared with baseline

values

3. The safety profiles of the two treatments were

similar

4. In patients with persistent asthma who require

inhaled short-acting β2-agonists while receiving

inhaled corticosteroids, transdermal tulobuterol

significantly improved PEF in a dose-dependent

Tuloplast monograph SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

manner[8]

Pediatric Asthma SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

1. Lin Q et al. 2013.

Tulobuterol patch Vs Oral Salbutamol. Background treatment of antihistamine, selective leukotriene receptor antagonist and glucocorticoid

Randomized, double blind

14 days 92 Mild and moderate acute asthmatic attack

1. On third day of treatment tulobuterol group had significantly lower symptom scores than the salbutamol group

2. On day 14 of treatment, tulobuterol group had a significantly lower cough score than the salbutamol group

3. Compared with oral salbutamol sulfate, tulobuterol patch has a better therapeutic efficacy and a higher safety in children with mild or moderate acute asthmatic attack.[9]

2. Katsunuma T et al. 2012.

Tulobuterol patch (TP) Vs Placebo patch

Randomized, multicenter, double-blind, placebo-controlled

1 year 86 Children with mild-to-moderate persistent asthma with URTI symptoms

1. The time to symptom resolution was significantly shorter (p = 0.001) and the total respiratory symptom score (p =0.0457) was significantly lower in the TP group than in the placebo group.

2. In young children with mild to-moderate asthma who had been treated with anti-inflammatory drugs, using the TP soon after the appearance of URTI symptoms led to quicker resolution of respiratory symptoms and lower respiratory symptom scores.[10]

3. Katsunuma T et al. 2013.

Tulobuterol patch 1-2 mg daily plus LTRA Vs Oral sustained

Multicenter, Randomized, open label

4 weeks 64 Children(4-12 years) with pediatric asthma on on long

1. Tulobuterol patch elicited significantly greater improvements in % PEF measured in the morning and before bedtime compared with sustained-release theophylline in children on long-term LTRA therapy.

2. Effects were observed without worsening of

Tuloplast monograph SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

release theophylline 4- mg/kg daily plus LTRA

term LTRA therapy

Fractional Exhaled Nitric Oxide (FeNO) indicating that it does not exacerbate airway inflammation in children.

3. Short-term continuous use of a transdermal β2 agonist is an effective therapy for pediatric asthma without inducing airway inflammation.[11]

COPD SN Author year Test drug

Study Design Duration

of the treatment

N Patients Conclusion

1. Mochizuki H et al. 2013.

Transdermal tulobuterol patch (TP 2 mg once daily) Vs Inhaled Salmeterol 50 micro g twice daily

Randomized, Crossover

44 Treatment naïve, elderly, moderate to severe COPD

1. The overall adherence rate was 90.3 ± 1.6% for TP and 75.5 ± 2.9% for salmeterol (P <0.001)

2. 6 minute walking distance and quality of life

(QOL) were significantly improved from baseline after TP, but not after salmeterol treatment.

3. Adherence levels were higher overall with TP than with inhaled salmeterol, and more stable across age groups and Mini mental State Examination (MMSE) levels

4. TP might be a favorable treatment option for COPD patients with poor adherence to an inhaled LABA [12]

2. Abe T et al. 2011.

Inhaled Tiotropium 18 micro g once daily plus transdermal tulobuterol 2 mg once daily (Tio plus Tulo) VS Inhaled Tiotropium 18

Randomized crossover

4 weeks each treatment

16 Clinically stable COPD with Forced Expiratory Volume in 1 s (FEV1) 30-80% of the predicted value

1. Tio plus Tulo was associated with significantly greater improvements than Tio in Impulse Oscillaion (IOS)-assessed markers of resistance (R5 and R5-R20), reactance and reactance area, from baseline to week 4.

2. Tio plus Tulo improved symptoms of dyspnea to a significantly greater extent than Tio alone.

3. Improvement from baseline in the impact component of SGRQ was significantly greater with Tio plus Tulo than with Tio alone. [13]

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micro g once daily (TIo)

3. Ichinose M et al. 2010.

Inhaled Tiotropium 18 micro g with transdermal tulobuterol 2 mg (Tio + Tulo) Vs Inhaled Tiotropium 18 micro g (Tio)

Randomized, Double blind

8 weeks 103 COPD patients

1. Percentage change in Inspiratory Capacity morning and evening peak expiratory flow on spirometry were significantly greater in the Tio plus Tulo group than in the Tio group.

2. Significant improvement in St. George Respiratory Questionnaire (SGRQ) observed only in Tio plus tulo group.

3. The benefits observed may be due to may be due to a reduction in pulmonary hyperinflation resulting from improvement of peripheral airflow obstruction through tulobuterol via the systemic circulation[14]

4. Fukuchi Y et al.2005.

Tulobuterol patch Vs Inhaled salmeterol

Multicenter, open-label randomized study

12 weeks 92 Clinically stable COPD patients

1. FEV1, FVC, and PEF improved during treatment in both groups compared with baseline, with no significant between group differences

2. The total St George's Respiratory Questionnaire (SGRQ) score was significantly improved relative to baseline in the tulobuterol group at 8 weeks, but not in the salmeterol group at all timepoints.

3. Compliance with the treatment regimen was significantly better in the tulobuterol than in the salmeterol group.

4. Once-daily transdermal sustained-release tulobuterol is as effective or better than the inhaled long-acting beta2-agonist salmeterol in the management of stable COPD, with significant effects on quality of life.[15]

Tuloplast monograph 5. Minami S et al.

2007. Transdermal tulobuterol patch (TP) Vs Theophylline

Randomized, controlled crossover study

4 weeks each treatment

16 COPD 1. Patients receiving TP exhibited significant improvement in the number and ease of sputum expectorations and in cough frequency score and wheezing severity score compared with baseline with corresponding no significant improvement in theophylline group.

2. Similar results were obtained for Assessment of quality of life by the St. George’s Hospital Respiratory Questionnaire.

3. Treatment of COPD patients with TP is more effective than with theophylline.[16]

6. Ichikawa T, Sugiura H. 2013.

Tulobuterol Patch

Review 1. Because the tulobuterol patch is easy to use and

requires only once-daily application, treatment adherence in patients using the patch is superior to that of other therapies.

2. The tulobuterol patch is currently used for the long-term treatment of patients with asthma and chronic obstructive pulmonary disease[17]

7. Tamura G, Ohta K. 2007.

Internet-based questionnaire study

1470 Asthma, COPD and parents of children with asthma

1. Among asthmatic patients, the percentage of those who selected ‘‘taking as prescribed’’ was 52.7% for inhalant users and 83.2% for Transdermal Patch-Long Acting Beta2 Agonist(TP-LABA users). Same values were 54.7% and 86.6%. respectively in COPD patients.

2. 83.3% reported once daily usage as the preferred frequency of administration

3. Transdermal tulobuterol patch, which is administered once daily as a long-acting, Beta2

agonist, appeared to be useful for long-term control of both asthma and COPD.[18]

Tuloplast monograph

Tuloplast monograph

TRIAL SUMMARY REFERENCES

1. Horiguchi T et al. Clinical evaluation of a transdermal therapeutic system of the beta2-

agonist tulobuterol in patients with mild or moderate persistent bronchial asthma.

Arzneimittelforschung.2004;54(5):280-5.

2. Kato H, Nagata O, Yamazaki M, Suzuki T, Nakano Y. Development of transdermal

formulation of tulobuterol for the treatment of bronchial asthma. Yakugaku

Zasshi. 2002 ;122(1):57-69.

3. Su N et al. The efficacy and safety of tulobuterol tape in mild and moderate persistent

asthma patients. Zhonghua Nei Ke Za Zhi. 2007 ;46(1):39-42

4. Burioka N et al. Alteration of the circadian rhythm in peak expiratory flow of nocturnal

asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol

chronotherapy. Chronobiol Int. 2005;22(2):383-90

5. Nishiyama O et al. Comparison of the effects of tulobuterol patch and salmeterol in

moderate to severe asthma. Clin Exp Pharmacol Physiol. 2006 ;33(11):1016-21.

6. Kume H et al. Effects of sustained-release tulobuterol on asthma control and beta-

adrenoceptor function. Clin Exp Pharmacol Physiol. 2002 ;29(12):1076-83.

7. Hozawa S. Haruta Y, Terada M, Yamakido M. Effects of the addition of Beta2-agonist

tulobuterol patches to inhaled corticosteroid in patients with asthma. Allergol Int. 2009

;58(4):509-18

8. Tamura G et al. Effect of Transdermal Tulobuterol Added to Inhaled Corticosteroids in

Asthma Patients. Allergology International. 2005;54:615-20

9. Lin Q, Liu QH, Bao YX. Efficacy and safety of tulobuterol patch versus oral salbutamol

sulfate in children with mild or moderate acute attack of bronchial asthma: a comparative

study. Zhongguo Dang Dai Er Ke Za Zhi. 2013;15(6):462-5.

10. Katsunuma T et al. Protective Effect of Tulobuterol Patch on the Long-term Management

of Asthma in Young Children Study Group. Effects of the tulobuterol patch on the

treatment of acute asthma exacerbations in young children. Allergy Asthma Proc.2012

;33(3):e28-34.

11. Katsunuma T et al. Effects of transdermal tulobuterol in pediatric asthma patients on long-

term leukotriene receptor antagonist therapy: results of a randomized, open-label,

multicenter clinical trial in Japanese children aged 4-12 years. Allergol Int. 2013 ;62(1):37-

43

12. Mochizuki H, Nanjo Y, Takahashi H. Better adherence to a transdermal tulobuterol patch

than inhaled salmeterol in elderly chronic obstructive pulmonary disease patients. Geriatr

Gerontol Int. 2013 ;13(2):398-404.

13. Abe T et al. Effects of inhaled tiotropium plus transdermal tulobuterol versus tiotropium

alone on impulse oscillation system (IOS)-assessed measures of peripheral airway

resistance and reactance, lung function and quality of life in patients with COPD: a

randomized crossover study. Pulm Pharmacol Ther. 2011 ;24(5):617-24

Tuloplast monograph

14. Ichinose M et al. Beta-2 Agonist Research and Evaluation Committee in COPD (BAREC)

Study Group. Additive effects of transdermal tulobuterol to inhaled tiotropium in patients

with COPD. Respir Med. 2010 ;104(2):267-74

15. Fukuchi Y et al. Clinical efficacy and safety of transdermal tulobuterol in the treatment of

stable COPD: an open-label comparison with inhaled salmeterol. Treat Respir Med.

2005;4(6):447-55

16. Minami S et al. Clinical efficacy of the transdermal tulobuterol patch in patients with

chronic obstructive pulmonary disease: a comparison with slow-release theophylline. Intern

Med. 2008;47(6):503-9

17. Ichikawa T, Sugiura H. Long-term safety, efficacy, and patient acceptability of the

tulobuterol patch. Research and Reports in Transdermal Drug Delivery 2013:2 9–18.

18. Tamura G, Ohta K. Adherence to treatment by patients with asthma or COPD: comparison

between inhaled drugs and transdermal patch. Respir Med. 2007;101(9):1895-902

Tuloplast monograph

For the use of Registered Medical Practitioner or a Hospital or a Laboratory only

Tuloplast Pack Insert

DESCRIPTION & COMPOSITION

Tulobuterol is a member of long acting β2 receptor agonist family. Its chemical name is (RS) -2-

tert-Butylamino-1- (2-chlorophenyl) ethanol and molecular formula is C 12 H 18 ClNO. Its

structural formula is depicted below:

Tulobuterol is a white crystal or crystalline powder without odor. It is very soluble in methanol,

ethanol (95) or acetic acid (100) and practically insoluble in water. Tulobuterol is volatilized.

Methanol solution (1→20) shows no optical rotation.

Brand name Tuloplast 0.5 Tuloplast 1 Tuloplast 2

Ingredient/contents Tulobuterol 0.5 mg in

each patch Tulobuterol 1 mg in

each patch Tulobuterol 2 mg in

each patch

Description

Square adhesive skin patch with rounded corners supporting a colorless

translucent ointment on a white support and coating the surface of

ointment with white liner

Appearance/Size

2.5 cm2

5 cm2

10 cm2

CLINICAL PHARMACOLOGY

Pharmacodynamics

Tulobuterol is a directly acting sympathomimetic and has selective β2 receptor stimulating activity.

Binding of Tulobuterol to β2 receptor leads to activation of adenylate cyclase enzyme, conversion

of ATP to cAMP and suppression of contraction of bronchial smooth muscles.

Pharmacokinetics

Bioequivalence testing

The concentration of Tulobuterol in plasma was measured (crossover method) after single

transdermal application (chest, 24 hours) of Tulobuterol Patch 0.5 mg, 1 mg and 2 mg and

Tuloplast monograph

standardized preparation corresponding to each standard to healthy adult males, and the statistical

analysis of pharmacokinetic parameters (AUC, Cmax) confirmed bioequivalence for both drugs.

(The usual dose in adults is 2 mg per dose as Tulobuterol.)

Pharmacokinetic parameters during application of Tulobuterol Patch Dose

(No. of

cases)

Drug administered Cmax

(ng/mL)

Tmax

(hr)

T1/2

(hr)

AUC0-48hr

(ng•hr/mL)

0.5 mg

[n=23]

Tulobuterol Patch 0.5 mg 0.48 ± 0.22 11.4 ± 4.1 11.1 ± 4.4 10.75 ± 7.65

Standardized preparation (adhesive skin patch 0.5

mg) 0.42 ± 0.20 15.4 ± 5.0 10.6 ± 4.2 10.67 ± 7.26

1 mg

[n=24]

Tulobuterol Patch 1 mg 0.59 ± 0.32 9.1 ± 2.1 10.4 ± 1.9 11.09 ± 6.86

Standardized preparation (adhesive skin patch 1

mg) 0.56 ± 0.27 11.5 ± 3.7 9.7 ± 1.3 12.10 ± 7.35

2 mg

[n=24]

Tulobuterol Patch 2 mg 1.29 ± 0.60 11.0 ± 2.7 11.0 ± 3.4

27.62 ±

18.77

Standardized preparation (adhesive skin patch 2

mg) 1.24 ± 0.63 14.5 ± 4.5 10.0 ± 4.5

29.65 ±

20.62

(Mean ± S.D.)

The plasma concentration-time graph of Tulobuterol Patch against standardized preparation is

depicted below.

INDICATIONS

For treatment of patients with Asthma and COPD without co-morbidity

DOSAGE AND ADMINISTRATION

Once daily, apply the patch to chest, back, or upper arm as per the following dosage regimen.

• For children aged 6 months to 3 years : 0.5 mg

• For children aged 3 to 9 years : 1.0 mg

• For adults and children aged > 9 years: 2.0 mg

USE IN SPECIAL POPULATIONS

Pregnancy and Lactation

Tulobuterol may be applied to pregnant women or women who may be pregnant only when

medical benefits outweigh the risk. [The safety of Tulobuterol in pregnancy has not been

established.]

If Tulobuterol is applied to nursing mothers, breast feeding should be avoided. [Transfer of

Tulobuterol into milk has been reported in animal studies (rat).]

TULOBUTEROL PATCH 2 mg Standardized preparation (adhesive skin patch 2 mg) Mean ±SD (n=24) Mean±SD (n=24)

Time after application (hr)

Detachment

Pla

sma

con

cen

trat

ion o

f T

UL

OB

UT

ER

OL

(n

g/m

L)

Tuloplast monograph

Pediatric Use

The safety of Tulobuterol has not been established in infants less than 6 months of age.

[Few experience of use.]

The safety of long term use of Tulobuterol has not been established in children. [Few

experience of use.]

Elderly population

Since physiological function is generally weakened in elderly people, Tulobuterol should be

carefully applied, e.g., by starting with lower dose.

CONTRAINDICATIONS Should not be used in the patients with a history of hypersensitivity to components of this drug

PRECAUTIONS

Careful Administration (Tulobuterol should be applied with care in the following patients.)

1) Patients with hyperthyroidism [Symptoms may be aggravated.]

2) Patients with hypertension [Blood pressure may be increased.]

3) Patients with heart disorder [Palpitation or arrhythmia may occur.]

4) Patients with diabetes mellitus [Glucose metabolism and blood glucose may increase.]

5) Patients with atopic dermatitis [Pruritus or redness may appear on application site.]

6) Elderly patients [Preferable to start with lower dose]

Important Precautions

1) Anti-inflammatory drugs such as inhaled steroids are essential for long-term management

of bronchial asthma. Tulobuterol should be applied concomitantly only if no improvement

of symptoms is noted with steroids or concomitant treatment with inhaled steroids are

considered appropriate according to the severity of patients’s condition. Since Tulobuterol

is not an alternative anti-inflammatory drug such as inhaled steroids, careful instruction

should be given to the patients, the patient's guardian or other appropriate designated

person that the patients should not reduce or discontinue the inhaled steroids, etc without a

physician advice and to use Tulobuterol alone even if the patients feel improvement of

symptoms with the use of Tulobuterol.

2) Careful instruction should be given to the patients, the patient's guardian or other

appropriate designated person that the patients should use other appropriate drugs such as

short-acting beta-stimulator for acute attack occurred during application of Tulobuterol in

the long-term management for the treatment of bronchial asthma.

Further, if the doses of those drugs are increased or they become ineffective, careful

instruction should be given to the patients, the patient's guardian or other appropriate

designated person that the patients should visit medical institutions to receive treatment as

soon as possible since asthma may not be adequately controlled. As this condition may be

life-threatening, intensification of anti-inflammatory therapy should be pursued.

3) If Tulobuterol is ineffective even when properly used according to DOSAGE AND

ADMINISTRATION (approximately one to two weeks as a guide), application should be

Tuloplast monograph

discontinued as Tulobuterol is considered inappropriate. In addition, proper instruction and

adequate follow-up should be provided for pediatric use.

4) As continued use of Tulobuterol beyond the dose range may cause arrhythmia or

occasionally cardiac arrest, caution should be given not to use beyond the dose limit.

DRUG INTERACTIONS

Drug Clinical Symptoms Mechanism

Catecholamine drugs

like adrenaline,

isoproterenol, etc.

Arrhythmia or occasionally

cardiac arrest.

Tulobuterol and catecholamine drugs

both have a sympathomimetic effect

Xanthine

derivatives :

theophylline,

aminophylline

hydrate,

diprophylline etc.

Arrhythmia due to hypokalemia

may occur.

Tulobuterol and xanthine derivatives

both have an effect of cellular uptake of

potassium

Steroid drugs such as

prednisolone,

betamethasone,

hydrocortisone, etc.

Arrhythmia due to hypokalemia

may occur.

Steroids increase potassium excretion

into urine.

Diuretics such as

trichlormethiazide,

furosemide,

acetazolamide, etc.

Arrhythmia due to hypokalemia

may occur.

Diuretics increase potassium excretion

into urine.

ADVERSE REACTIONS

Clinically significant adverse reactions

Anaphylactoid symptoms

Since anaphylactoid symptoms may occur, the patient should be closely observed. If any

symptoms such as dyspnea, generalized flushing, angioedema and urticaria are noted, application

should be discontinued and appropriate measures should be taken.

Serious decrease in serum potassium level

Serious decreased serum potassium has been reported with β2 stimulant. Since the serum

potassium-lowering effect of β2 stimulant may increase with concomitant use of xanthine

derivatives, steroids and diuretics, special caution should be given in patients with severe asthma.

Tuloplast monograph

Furthermore, hypoxemia may enhance the effect of decreased serum potassium level on cardiac

rhythm. In such case, serum potassium level should be monitored.

Other Adverse Reactions

Incidence unknown

Hypersensitivity

(Caution)

Rash, pruritus, urticaria

Cardiovascular Palpitations, facial flushing, arrhythmia, tachycardia

Neuropsychiatric Tremor, headache, insomnia, general feeling of malaise, dizziness,

excitement, numbness, muscle spasms, heat sensation, feeling of stiffness

Gastrointestinal Nausea and vomiting, loss of appetite, diarrhea, stomach discomfort

Hepatic AST (GOT) increased, ALT (GPT) rise

hematologic Eosinophil count increased

Dermatologic Application site pruritus, application site erythema, contact dermatitis,

application site pain, application site discoloration

Other CK (CPK) increased, decrease in serum potassium levels, chest pain, edema,

dry mouth, muscle pain

Caution: If any symptoms are observed, application of Tulobuterol should be discontinued

PRECAUTIONS FOR APPLICATION

Before applying Tuloplast clean and dry the application site.

Choose a new site each time to avoid cutaneous irritation.

Place Tuloplast on an area that is out of reach of children who may peel it off.

Tuloplast should not be used within the wound as animal studies (rat) showed an increase

in the blood level when Tuloplast was applied on the compromised skin.

PRECAUTION FOR HANDLING

Precautions for use and storage

Provide Tuloplast in the inner package to the patients and instruct them to take it out from the inner

package when used.

Safety study

Among heat sealing packages used for each drug, those stored for 3 years under storage condition at

25°C and 60%RH met the standards of all test parameters including quantitative test.