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BRALTUS 10 MICROGRAM PER DELIVERED DOSE INHALATION POWDER HARD CAPSULE

Active substance(s): TIOTROPIUM BROMIDE / TIOTROPIUM BROMIDE / TIOTROPIUM BROMIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Braltus 10 microgram per delivered dose inhalation powder, hard capsule

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 16 micrograms of tiotropium bromide, equivalent to
13 micrograms of tiotropium.
The delivered dose (the dose that leaves the mouthpiece of the Zonda inhaler)
is 10 micrograms of tiotropium per capsule
Excipient with known effect
Each capsule contains 18 milligrams lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Inhalation powder, hard capsule.
Colourless and transparent, size 3 capsules, containing white powder.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Braltus is indicated as a maintenance bronchodilator treatment to relieve
symptoms in patients with chronic obstructive pulmonary disease (COPD).
Braltus is indicated for use in adults.

4.2

Posology and method of administration
Posology
Route of administration: Inhalation use.
Recommended Dose
Adults 18 years of age and older:
Inhalation of the contents of one capsule once daily with the Zonda inhaler.
Inhalation should be at the same time of day each day.
The recommended dose should not be exceeded.
The delivered dose of a single capsule (10 micrograms) is sufficient and is the
standard dose for treatment with Braltus..
Braltus capsules are for inhalation only; they must not be swallowed.
Braltus capsules must only be inhaled with the Zonda inhaler.
Special populations
Elderly patients can use tiotropium bromide at the recommended dose.
Patients with mild renal impairment (creatinine clearance >50 ml/min) can use
tiotropium bromide at the recommended dose. For patients with moderate to
severe impairment (creatinine clearance ≤50 ml/min) see section 4.4 and
section 5.2.
Hepatically impaired patients can use tiotropium bromide at the recommended
dose (see section 5.2).
Paediatric population
Braltus should not be used in children or adolescents under 18 years of age.
Safety and efficacy have not been established. No data are available.
There is no relevant use for tiotropium bromide in the paediatric population
for the indication of COPD.
The safety and efficacy of tiotropium bromide in cystic fibrosis in children and
adolescents aged less than 18 years have not been established. No data are
available.
Method of administration/instructions for Use and Handling
To ensure proper administration of the medicinal product, the patient should
be trained in the use of the inhaler by either the prescribing physician or by
other healthcare professionals.
The Zonda inhaler is especially designed for Braltus capsules; patients must
not use it to take any other medication. Braltus capsules must only be inhaled
using the Zonda inhaler. Patients must not use any other inhalers to take
Braltus capsules.

The Zonda inhaler should only be used with the bottle of capsules provided.
Do not reuse the inhaler for another bottle of capsules. Discard the Zonda
device after 30 uses 15 uses if used on conjunction with the 15 capsule
presentation)

1. Dust cap
2. Mouthpiece
3. Base
4. Piercing button
5. Centre chamber
1. Pull the cap upwards.

2. Hold the base of the inhaler firmly and open the mouthpiece by pulling it
upwards, in the direction of the arrow to open it.

3. Remove a Braltus capsule from the bottle immediately before use and close
the bottle tightly. Place one capsule in the capsule-shaped compartment in the
base of the inhaler. Do not store the capsule in the Zonda inhaler.

4. Never place a capsule directly into the mouthpiece.

5. Close the mouthpiece until a click is heard, leaving the cap open.

6. Hold the inhaler with the mouthpiece upwards, and press the piercing button
completely in only once. Release the button. This will pierce the capsule and
allows the medication to be released when the patient breathes in.

7. Breathe out fully. It is important to do this away from the mouthpiece.
Avoid breathing into the mouthpiece at any time.

8. Place the mouthpiece in your mouth and keep your head in an upright
posistion. Close your lips around the mouthpiece and breathe in slowly and
deeply enough to hear or feel the capsule vibrating inside the compartment.
Hold your breathe for as long as you comfortably can whilst taking the inhaler
out of your mouth. Then breathe normally. Repeat steps 7 and 8 to empty the
capsule completely.

9. After use, open the mouthpiece again, and tip out the empty capsule. Close
the mouthpiece and cap, and store the Zonda inhaler.
9

Braltus capsules contain only a small amount of powder, so that the capsule is
only partially filled.
If necessary, the patient may wipe the mouthpiece of the Zonda inhaler after
use with a dry cloth or tissue.

4.3

Contraindications
Hypersensitivity to the active substance tiotropium bromide, atropine or its
derivatives, e.g. ipratropium or oxitropium, or to any of the excipients listed in
section 6.1, including lactose monohydrate which contains milk protein.

4.4

Special warnings and precautions for use
Tiotropium bromide, as a once daily maintenance bronchodilator, should not
be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue
therapy.
Immediate hypersensitivity reactions may occur after administration of
tiotropium bromide inhalation powder.
Consistent with its anticholinergic activity, tiotropium bromide should be used
with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or
bladder-neck obstruction. (see section 4.8).
As with other inhalation therapy, paradoxical bronchospasm may occur with
an immediate increase in wheezing and shortness of breath after dosing.
Paradoxical bronchospasm responds to a
rapid-acting bronchodilator and should be treated straightaway. Braltus
should be discontinued immediately, the patient assessed and alternative
therapy instituted if necessary.
Tiotropium should be used with caution in patients with recent myocardial
infarction <6 months; any unstable or life threatening cardiac arrhythmia or
cardiac arrhythmia requiring intervention or a change in drug therapy in the
past year; hospitalisation for heart failure (NYHA Class III or IV) within the
past year. These patients were excluded from the clinical trials and these
conditions may be affected by the anticholinergic mechanism of action.
As plasma concentration increases with decreased renal function in patients
with moderate to severe renal impairment (creatinine clearance ≤50 ml/min),
tiotropium bromide should be used only if the expected benefit outweighs the
potential risk.There is no long term experience in patients with severe renal
impairment (see section 5.2).
Patients should be cautioned to avoid getting the drug powder into their eyes.
They should be advised that this may result in precipitation or worsening of
narrow-angle glaucoma, eye pain or discomfort, temporary blurring of vision,

visual halos or coloured images in association with red eyes from conjunctival
congestion and corneal oedema. Should any combination of these eye
symptoms develop, patients should stop using tiotropium bromide and consult
a specialist immediately.
Dry mouth, which has been observed with anti-cholinergic treatment, may in
the long term be associated with dental caries.
Tiotropium bromide should not be used more frequently than once daily (see
section 4.9).
Each capsule contains 18 mg lactose monohydrate. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine. The excipient lactose may contain trace
amounts of milk proteins which may cause reactions in those with severe
hypersensitivity or allergy to milk protein.

4.5

Interaction with other medicinal products and other forms of interaction
Although no formal drug interaction studies have been performed, tiotropium
bromide inhalation powder has been used concomitantly with other drugs
without clinical evidence of drug interactions. These include sympathomimetic
bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in
the treatment of COPD.
Use of long-acting β2 agonists (LABA) or inhaled corticosteroids (ICS) was
not found to alter the exposure to tiotropium.
The co-administration of tiotropium bromide with other anticholinergic drugs
has not been studied and is therefore not recommended.

4.6

Fertility, pregnancy and lactation
Fertility
Clinical data on fertility are not available for tiotropium. A non-clinical study
performed with tiotropium showed no indication of any adverse effect on
fertility (see section 5.3).
Pregnancy
There is a very limited amount of data from the use of tiotropium in pregnant
women. Animal studies do not indicate direct or indirect harmful effects with
respect to reproductive toxicity at clinically relevant doses (see 5.3). As a

precautionary measure, it is preferable to avoid the use of Braltus during
pregnancy.
Breast-feeding
It is unknown whether tiotropium bromide is excreted in human breast milk.
Despite studies in rodents which have demonstrated that excretion of
tiotropium bromide in breast milk occurs only in small amounts, use of
tiotropium bromide is not recommended during breast-feeding. Tiotropium
bromide is a long-acting compound. A decision on whether to
continue/discontinue breast-feeding or to continue/discontinue therapy with
Braltus should be made taking into account the benefit of breast-feeding to the
child and the benefit of Braltus therapy to the woman.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. The occurrence of dizziness, blurred vision, or headache may
influence the ability to drive and use machinery.

4.8

Undesirable effects
Many of the listed undesirable effects can be assigned to the anticholinergic
properties of tiotropium bromide.
The frequencies assigned to the undesirable effects listed below are based on
crude incidence rates of adverse drug reactions (i.e. events attributed to
tiotropium) observed in the tiotropium group (9,647 patients) from 28 pooled
placebo-controlled clinical trials with treatment periods ranging from four
weeks to four years.
Frequency is defined using the following convention:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known
(cannot be estimated from the available data)

System Organ Class/MedDRA Preferred Term
Metabolism and nutrition disorders
Dehydration
Nervous system disorders
Dizziness
Headache
Taste disorders

Frequency
Not known
Uncommon
Uncommon
Uncommon

Insomnia
Eye disorders
Vision blurred
Glaucoma
Intraocular pressure increased
Cardiac disorders
Atrial fibrillation
Supraventricular tachycardia
Tachycardia
Palpitations
Respiratory, thoracic and mediastinal disorders
Pharyngitis
Dysphonia
Cough
Bronchospasm
Epistaxis
Laryngitis
Sinusitis
Gastrointestinal disorders
Dry mouth
Gastrooesophageal reflux disease
Constipation
Oropharyngeal candidiasis
Intestinal obstruction, including ileus paralytic
Gingivitis
Glossitis
Dysphagia
Stomatitis
Nausea
Dental caries
Skin and subcutaneous tissue disorders, immune
system disorders
Rash
Urticaria
Pruritus
Hypersensitivity (including immediate reactions)
Angioedema
Anaphylactic reaction
Skin infection, skin ulcer
Dry skin
Musculoskeletal and connective tissue disorders
Joint swelling
Renal and urinary disorders
Dysuria
Urinary retention
Urinary tract infection

Rare
Uncommon
Rare
Rare
Uncommon
Rare
Rare
Rare
Uncommon
Uncommon
Uncommon
Rare
Rare
Rare
Rare
Common
Uncommon
Uncommon
Uncommon
Rare
Rare
Rare
Rare
Rare
Rare
Not known
Uncommon
Rare
Rare
Rare
Rare
Not known
Not known
Not known

Not known
Uncommon
Uncommon
Rare

Allergic reactions
The excipient lactose may contain trace amounts of milk proteins which may
cause reactions in those with severe hypersensitivity or allergy to milk protein.

Tiotropium bromide should be discontinued immediately if a hypersensitivity
or allergic reaction occurs and the patient should then be managed in the usual
way.
Paradoxical bronchospasm
As with other inhalation therapy paradoxical bronchospasm may occur with an
immediate increase in wheezing and shortness of breath after dosing.
Paradoxical bronchospasm responds to a
rapid-acting bronchodilator and should be treated straightaway. Braltus
should be discontinued immediately, the patient assessed and alternative
therapy instituted if necessary.
Description of selected adverse reactions
In controlled clinical studies, the commonly observed undesirable effects were
anticholinergic undesirable effects such as dry mouth which occurred in
approximately 4% of patients.
In 28 clinical trials, dry mouth led to discontinuation in 18 of 9,647 tiotropium
treated patients (0.2%).
Serious undesirable effects consistent with anticholinergic effects include
glaucoma, constipation and intestinal obstruction including ileus paralytic as
well as urinary retention.
Other special population
An increase in anticholinergic effects may occur with increasing age.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
High doses of tiotropium bromide may lead to anticholinergic signs and
symptoms.
However, there were no systemic anticholinergic adverse effects following a
single inhaled dose of up to 340 microgram tiotropium bromide in healthy
volunteers. Additionally, no relevant adverse effects, beyond dry mouth, were
observed following 7 day dosing of up to 170 microgram tiotropium bromide
in healthy volunteers. In a multiple dose study in COPD patients with a
maximum daily dose of 43 microgram tiotropium bromide over four weeks no
significant undesirable effects have been observed.

Acute intoxication by inadvertent oral ingestion of tiotropium bromide
capsules is unlikely due to low oral bioavailability.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Other drugs for obstructive airway diseases,
inhalants, anticholinergics
ATC code: R03B B04
Mechanism of action
Tiotropium bromide is a long-acting, specific, muscarinic receptor antagonist,
in clinical medicine often called an anticholinergic. By binding to the
muscarinic receptors in the bronchial smooth musculature, tiotropium bromide
inhibits the cholinergic (bronchoconstrictive) effects of acetylcholine, released
from parasympathetic nerve endings. It has similar affinity to the subtypes of
muscarinic receptors, M1 to M5. In the airways, tiotropium bromide
competitively and reversibly antagonises the M3 receptors, resulting in
relaxation. The effect was dose dependent and lasted longer than 24 hours.
The long duration is probably due to the very slow dissociation from the M3
receptor, exhibiting a significantly longer dissociation half-life than
ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is
topically (broncho-) selective when administered by inhalation, demonstrating
an acceptable therapeutic range before systemic anticholinergic effects may
occur.
Pharmacodynamic effects
The bronchodilation is primarily a local effect (on the airways), not a systemic
one. Dissociation from M2-receptors is faster than from M3, which in
functional in vitro studies, elicited (kinetically controlled) receptor subtype
selectivity of M3 over M2. The high potency and slow receptor dissociation
found its clinical correlate in significant and long-acting bronchodilation in
patients with COPD.
Cardiac electrophysiology
Electrophysiology: In a dedicated QT study involving 53 healthy volunteers,
tiotropium 18 microgram and 54 microgram (i.e. three times the therapeutic
dose) over 12 days did not significantly prolong QT intervals of the ECG.
Clinical efficacy and safety
The clinical development programme included four one-year and two sixmonth randomised, double-blind studies in 2663 patients (1308 receiving
tiotropium bromide). The one-year programme consisted of two placebocontrolled trials and two trials with an active control (ipratropium). The two

six-month trials were both, salmeterol and placebo controlled. These studies
included lung function and health outcome measures of dyspnea,
exacerbations and health-related quality of life.
Lung function
Tiotropium bromide, administered once daily, provided significant
improvement in lung function (forced expiratory volume in one second, FEV1
and forced vital capacity, FVC) within 30 minutes following the first dose
which was maintained for 24 hours. Pharmacodynamic steady state was
reached within one week with the majority of bronchodilation observed by the
third day. Tiotropium bromide significantly improved morning and evening
PEFR (peak expiratory flow rate) as measured by patient's daily recordings.
The bronchodilator effects of tiotropium bromide were maintained throughout
the one year period of administration with no evidence of tolerance.
A randomised, placebo-controlled clinical study in 105 COPD patients
demonstrated that bronchodilation was maintained throughout the 24 hour
dosing interval in comparison to placebo regardless of whether the drug was
administered in the morning or in the evening.
Clinical trials (up to 12 months)
Dyspnoea, Exercise tolerance
Tiotropium bromide significantly improved dyspnea (as evaluated using the
Transition Dyspnea Index.). This improvement was maintained throughout the
treatment period.
The impact of improvements in dyspnea on exercise tolerance was
investigated in two randomised, double-blind, placebo-controlled trials in 433
patients with moderate to severe COPD. In these trials, six weeks of treatment
with tiotropium bromide significantly improved symptom-limited exercise
endurance time during cycle ergometry at 75% of maximal work capacity by
19.7% (Trial A) and 28.3% (Trial B) compared with placebo).
Health-related Quality of Life
In a 9-month, randomized, double-blind, placebo-controlled clinical trial of
492 patients, tiotropium bromide improved health-related quality of life as
determined by the St. George's Respiratory Questionnaire (SGRQ) total score.
The proportion of patients treated with tiotropium which achieved a
meaningful improvement in the SGRQ total score (i.e. > 4 units) was 10.9%
higher compared with placebo (59.1% in the tiotropium bromide groups vs.
48.2% in the placebo group (p=0.029)). The mean difference between the
groups was 4.19 units (p=0.001; confidence interval: 1.69 – 6.68). The
improvements of the subdomains of the SGRQ-score were 8.19 units for
“symptoms”, 3.91 units for “activity” and 3.61 units for “impact on daily life”.
The improvements of all of these separate subdomains were statistically
significant.
COPD Exacerbations
In a randomized, double-blind, placebo controlled trial of 1,829 patients with
moderate to very severe COPD, tiotropium bromide statistically significantly

reduced the proportion of patients who experienced exacerbations of COPD
(32.2% to 27.8%) and statistically significantly reduced the number of
exacerbations by 19% (1.05 to 0.85 events per patient year of exposure). In
addition, 7.0% of patients in the tiotropium bromide group and 9.5% of
patients in the placebo group were hospitalized due to a COPD exacerbation
(p=0.056). The number of hospitalizations due to COPD was reduced by 30%
(0.25 to 0.18 events per patient year of exposure).
A one-year randomised, double-blind, double-dummy, parallel-group trial
compared the effect of treatment with 18 microgram tiotropium once daily
with that of 50 microgram salmeterol HFA pMDI twice daily on the incidence
of moderate and severe exacerbations in 7,376 patients with COPD and a
history of exacerbations in the preceding year.
Table 1: Summary of exacerbation endpoints
Tiotropium
Salmeterol 50
18 microgram
microgram
Endpoint
inhalation
HFA pMDI
powder4
N = 3669
N = 3707
Time [days] to
187
145
first
exacerbation1
Time to first
severe
(hospitalised)
exacerbation2
Patients with ≥1
exacerbation, n
1277 (34.4)
1414 (38.5)
3
(%)
Patients with ≥1
severe
(hospitalised)
262 (7.1)
336 (9.2)
exacerbation, n
(%)3

Ratio
(95% CI)

p-value

0.83
(0.770.90)

<0.001

0.72
(0.610.85)

<0.001

0.90
(0.850.95)

<0.001

0.77
(0.660.89)

<0.001

1

Time [days] refers to 1st quartile of patients. Time to event analysis was
done using Cox's proportional hazards regression model with (pooled) centre
and treatment as covariate; ratio refers to hazard ratio.
2
Time to event analysis was done using Cox's proportional hazards regression
model with (pooled) centre and treatment as covariate; ratio refers to hazard
ratio. Time [days] for the 1st quartile of patients cannot be calculated, because
proportion of patients with severe exacerbation is too low.
3
Number of patients with event were analysed using Cochran-MantelHaenszel test stratified by pooled centre; ratio refers to risk ratio.
4
Tiotropium 18 microgram inhalation powder delivers 10 microgram
tiotropium
Compared with salmeterol, tiotropium bromide increased the time to the first
exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard

ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium
bromide also increased the time to the first severe (hospitalised) exacerbation
(hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001).
Long-term clinical trials (more than 1 year, up to 4 years)
In a 4-year, randomised, double-blind, placebo-controlled clinical trial of
5,993 randomised patients (3,006 receiving placebo and 2,987 receiving
tiotropium bromide), the improvement in FEV1 resulting from tiotropium
bromide, compared with placebo, remained constant throughout 4 years. A
higher proportion of patients completed ≥ 45 months of treatment in the
tiotropium bromide group compared with the placebo group (63.8% vs.
55.4%, p<0.001). The annualized rate of decline of FEV1 compared to placebo
was similar between tiotropium bromide and placebo. During treatment, there
was a 16% reduction in the risk of death. The incidence rate of death was 4.79
per 100 patient years in the placebo group vs. 4.10 per 100 patient years in the
tiotropium group (hazard ratio (tiotropium/placebo) = 0.84, 95% CI = 0.73,
0.97). Treatment with tiotropium reduced the risk of respiratory failure (as
recorded through adverse event reporting) by 19% (2.09 vs. 1.68 cases per 100
patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 0.999).
Tiotropium active-controlled study
A long-term, large scale randomised, double-blind, active-controlled study
with an observation period up to 3 years has been performed to compare the
efficacy and safety of tiotropium bromide inhalation powder and tiotropium
bromide soft mist inhaler (5,694 patients receiving tiotropium bromide
inhalation powder; 5,711 patients receiving tiotropium bromide soft mist
inhaler). The primary endpoints were time to first COPD exacerbation, time to
all-cause mortality and in a sub-study (906 patients) trough FEV1 (pre-dose).
The time to first COPD exacerbation was numerically similar during the study
with tiotropium bromide inhalation powder and tiotropium bromide soft mist
inhaler (hazard ratio (tiotropium bromide inhalation powder/ tiotropium
bromide soft mist inhaler) 1.02 with a 95% CI of 0.97 to 1.08). The median
number of days to the first COPD exacerbation was 719 days for tiotropium
bromide inhalation powder and 756 days for tiotropium bromide soft mist
inhaler.
The bronchodilator effect of tiotropium bromide inhalation powder was
sustained over 120 weeks, and was similar to tiotropium bromide soft mist
inhaler. The mean difference in trough FEV1 for tiotropium bromide inhalation
powder versus tiotropium bromide soft mist inhaler was 0.010 L (95% CI 0.018 to 0.038 L).
In the post-marketing study comparing tiotropium bromide soft mist inhaler
and tiotropium bromide inhalation powder, all-cause mortality including vital
status follow up was similar during the study with tiotropium bromide
inhalation powder and tiotropium bromide soft mist inhaler (hazard ratio
(tiotropium bromide inhalation powder/tiotropium bromide soft mist inhaler)
1.04 with a 95% CI of 0.91 to 1.19).
Paediatric population
The European Medicines Agency has waived the obligation to submit results
of studies with tiotropium bromide in all subsets of the paediatric population

in COPD and cystic fibrosis (see section 4.2 for information on paediatric
use).

5.2

Pharmacokinetic properties
Tiotropium bromide is a non-chiral quaternary ammonium compound and is
sparingly soluble in water. Tiotropium bromide is administered by dry powder
inhalation. Generally with the inhaled route of administration, the majority of
the delivered dose is deposited in the gastro-intestinal tract, and to a lesser
extent in the intended organ of the lung. Many of the pharmacokinetic data
described below were obtained with higher doses than recommended for
therapy.
Absorption
Following dry powder inhalation by young healthy volunteers, the absolute
bioavailability of 19.5% suggests that the fraction reaching the lung is highly
bioavailable. Oral solutions of tiotropium have an absolute bioavailability of
2-3%. Maximum tiotropium plasma concentrations were observed 5-7 minutes
after inhalation.
At steady state, peak tiotropium plasma levels in COPD patients were 12.9
pg/ml and decreased rapidly in a multicompartmental manner. Steady state
trough plasma concentrations were 1.71 pg/ml. Systemic exposure following
the inhalation of tiotropium bromide inhalation powder was similar to
tiotropium inhaled via the soft mist inhaler.
Distribution
Tiotropium has a plasma protein binding of 72% and shows a volume of
distribution of 32 L/kg. Local concentrations in the lung are not known, but
the mode of administration suggests substantially higher concentrations in the
lung. Studies in rats have shown that tiotropium bromide does not penetrate
the blood-brain barrier to any relevant extent.
Biotransformation
The extent of biotransformation is small. This is evident from a urinary
excretion of 74% of unchanged substance after an intravenous dose to young
healthy volunteers. The ester tiotropium bromide is nonenzymatically cleaved
to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid)
that are inactive on muscarinic receptors. In-vitro experiments with human
liver microsomes and human hepatocytes suggest that some further drug
(<20% of dose after intravenous administration) is metabolised by cytochrome
P450 (CYP) dependent oxidation and subsequent glutathionconjugation to a
variety of Phase II-metabolites.
In vitro studies in liver microsomes reveal that the enzymatic pathway can be
inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and
gestodene. Thus CYP 2D6 and 3A4 are involved in metabolic pathway that is
responsible for the elimination of a smaller part of the dose. Tiotropium

bromide even in supra-therapeutic concentrations does not inhibit CYP 1A1,
1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.
Elimination
The effective half-life of tiotropium ranges between 27-45h in COPD patients.
Total clearance was 880 ml/min after an intravenous dose in young healthy
volunteers. Intravenously administered tiotropium is mainly excreted
unchanged in urine (74%). After dry powder inhalation by COPD patients in
steady-state, urinary excretion is 7% (1.3 micrograms) of the unchanged drug
over 24 hours, the remainder being mainly non-absorbed drug in gut that is
eliminated via the faeces. The renal clearance of tiotropiumexceeds the
creatinine clearance, indicating secretion into the urine. After chronic once
daily inhalation by COPD patients, pharmacokinetic steady state was reached
by day 7 with no accumulation thereafter.
Linearity/non-linearity
Tiotropium demonstrates linear pharmacokinetics in the therapeutic range
independent of the formulation.
Special patient populations
Older people: As expected for all predominantly renally excreted drugs,
advanced age was associated with a decrease of tiotropium renal clearance
(365 mL/min in COPD patients <65 years to 271 mL/min in COPD patients
≥65 years). This does not result in a corresponding increase in AUC0-6,ss or
Cmax,ss values.
Renal impairment: Following once daily inhaled administrations of tiotropium
to steady-state COPD patients, mild renal impairment (CLCR 50-80 mL/min)
resulted in slightly higher AUC0-6,ss (between 1.8-30% higher) and similar
Cmax,ss values compared to patients with normal renal function (CLCR >80
mL/min)..
In COPD patients with moderate to severe renal impairment (CLCR <50
mL/min) the intravenous administration of tiotropium resulted in doubling of
the total exposure (82% higher AUC0-4h and 52% higher Cmax) compared to
COPD patients with normal renal functions, which was confirmed by plasma
concentrations after dry powder inhalation.
Hepatic impairment: Liver insufficiency is not expected to have any relevant
influence on tiotropium pharmacokinetics. Tiotropium is predominantly
cleared by renal elimination (74% in young healthy volunteers) and simple
non-enzymatic ester cleavage to pharmacologically inactive products.
Japanese COPD Patients: In cross trial comparison, mean peak tiotropium
plasma concentrations 10 minutes postdosing at steady-state were 20% to 70%
higher in Japanese compared to Caucasian COPD patients following inhalation
of tiotropium but there was no signal for higher mortality or cardiac risk in
Japanese patients compared to Caucasian patients. Insufficient
pharmacokinetic data is available for other ethnicities or races.
Paediatric population: See section 4.2

Pharmacokinetic/pharmacodynamic relationship
There is no direct relationship between pharmacokinetics and
pharmacodynamics.

5.3

Preclinical safety data
Many effects observed in conventional studies of safety pharmacology,
repeated dose toxicity, and reproductive toxicity could be explained by the
anticholinergic properties of tiotropium bromide. Typically in animals reduced
food consumption, inhibited body weight gain, dry mouth and nose, reduced
lacrimation and salivation, mydriasis and increased heart rate were observed.
Other relevant effects noted in repeated dose toxicity studies were: mild
irritancy of the respiratory tract in rats and mice evinced by rhinitis and
epithelial changes of the nasal cavity and larynx, and prostatitis along with
proteinaceous deposits and lithiasis in the bladder in rats.
Harmful effects with respect to pregnancy, embryonal/foetal development,
parturition or postnatal development could only be demonstrated at maternally
toxic dose levels. Tiotropium bromide was not teratogenic in rats or rabbits. In
a general reproduction and fertility study in rats, there was no indication of
any adverse effect on fertility or mating performance of either treated parents
or their offspring at any dosage.
The respiratory (irritation) and urogenital (prostatitis) changes and
reproductive toxicity were observed at local or systemic exposures more than
five-fold the therapeutic exposure. Studies on genotoxicity and carcinogenic
potential revealed no special hazard for humans.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate (which contains milk protein)
Capsule composed of hydroxypropylmethylcellulose (HPMC), commonly
known as Hypromellose.

6.2

Incompatibilities

Not applicable

6.3

Shelf life
24 months
After first opening: 30 days (15 capsule bottle) or 60 days (30 capsule bottle)

6.4

Special precautions for storage
Keep the bottle tightly closed. Store in the original package to protect from
moisture.
Do not refrigerate or freeze.

6.5

Nature and contents of container
High density polyethylene (HDPE) bottles closed with polypropylene (PP)
screw-caps with polyethylene (PE) safety ring and Low density polyethylene
(LDPE) desiccant capsule containing silica gel. Each bottle contains 15 or 30
capsules, supplied in a carton with a Zonda inhaler.
The Zonda inhaler is a single dose inhalation device with a green body and cap
and a white push button,made from acrylonitrile butadiene styrene (ABS)
plastic materials and stainless steel.
Multipacks containing either 60 capsules (2 packs of 30), and 2 Zonda inhalers
or 90 capsules (3 packs of 30), and 3 Zonda inhalers.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
TEVA UK Limited,
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex, BN22 9AG
UNITED KINGDOM

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/1870

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/06/2016

10

DATE OF REVISION OF THE TEXT
24/06/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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