S p iriva
H andiH alS r
'(tiotropium bromide inhalation powder)
Brief Summary of Prescribing Information
Do Not Swallow Spiriva Capsules
For Use With HandiHaler Only
FOR ORAL INHALATION ONLY
^ only
INDICATIONS AND USAGE
SPIRIVA HandiHaler is indicated for the long-term, once-daily, maintenance treatment of bron-
chospasm associated with chronic obstructive pulmonary disease (COPD), including chronic
bronchitis and emphysema.
CONTRAINDICATIONS
SPIRIVA HandiHaler is contraindicated in patients with a history of hypersensitivity to atropine
or its derivatives, including ipratropium, or to any component of this product.
WARNINGS
SPIRIVA HandiHaler is intended as a once-daily maintenance treatment for COPD and is not
indicated for the initial treatment of acute episodes of bronchospasm. i.e., rescue therapy.
Immediate hypersensitivity reactions, including angioedema. may occur after administration of
SPIRIVA HandiHaler. If such a reaction occurs, therapy with SPIRIVA HandiHaler should be
stopped at once and alternative treatments should be considered.
Inhaled medicines, including SPIRIVA HandiHaler. may cause paradoxical bronchospasm. If
this occurs, treatment with SPIRIVA HandiHaler should be stopped and other treatments
considered.
PRECAUTIONS
General
As an anticholinergic drug. SPIRIVA HandiHaler may potentially worsen symptoms and signs
associated with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction and
should be used with caution in patients with any of these conditions.
As a predominantly renally excreted drug, patients with moderate to severe renal impairment (cre-
atinine clearance of <50 miymin) treated with SPIRIVA HandiHaler should be monitored closely
(see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations,
Renalty-impaired
Patients).
Information for Patients
It is important for patients to understand how to correctly administer SPIRIVA capsules using
the HandiHaler inhalation device (see Patient’s Instructions for Use). SPIRIVA capsules
should only be administered via the HandiHaler device and the HandiHaler device should not
be used for administering other medications. The contents of SPIRIVA capsules are for oral
inhalation only and must not be swallowed.
Capsules should always be stored in sealed blisters. Remove only one capsule immediately
before use. or its effectiveness may be reduced. Additional capsules that are exposed to air
(i.e., not intended for immediate use) should be discarded.
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red
eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle
glaucoma. Should any of these signs and symptoms develop, consult a physician immediate-
ly. Miotic eye drops alone are not considered to be effective treatment.
Care must be taken not to allow the powder to enter into the eyes as this may cause blurring
of vision and pupil dilation.
SPIRIVA HandiHaler is a once-daily maintenance bronchodilator and should not be used for
immediate relief of breathing problems, i.e.
. as a rescue medication.
Drug Interactions
SPIRIVA HandiHaler has been used concomitantly with other drugs commonly used in COPD
without increases in adverse drug reactions. These include short-acting and long-acting sym-
pathomimetic (beta-agonists) bronchodilators. methylxanthines, and oral and inhaled steroids.
However, the co-administration of SPIRIVA HandiHaler with other anticholinergic-containing
drugs (e.g., ipratropium) has not been studied and is therefore not recommended.
Drug/Laboratory Test Interactions
None known.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropi-
um doses up to 0.059 mg/kg/day. in an 83-week inhalation study in female mice at doses up
to 0.145 mg/kg/day. and in a 101-week inhalation study in male mice at doses up to
0.002 mg/kg/day. These doses correspond to 25.35. and 0.5 times the Recommended Human
Daily Dose (RHDD) on a mg/m2 basis, respectively. These dose multiples may be over-esti-
mated due to difficulties in measuring deposited doses in animal inhalation studies.
Tiotropium bromide demonstrated no evidence of mutagenicity or dastogenicity in the following
assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the
chromosomal aberration assays in human lymphocytes
in vitro
and mouse micronucleus forma-
tion
in vivo,
and the unscheduled DNA synthesis in primary rat hepatocytes
in vitro
assay.
In rats, decreases in the number of corpora lutea and the percentage of implants were noted
at inhalation tiotropium doses of 0.078 mg/kg/day or greater (approximately 35 times the
RHDD on a mg/m-’ basis). No such effects were observed at 0.009 mg/kg/day (approximately
4 times than the RHDD on a mg/m2 basis). The fertility index, however, was not affected at
inhalation doses up to 1.689 mg/kg/day (approximately 760 times the RHDD on a mg/m2
basis). These dose multiples may be over-estimated due to difficulties in measuring deposited
doses in animal inhalation studies.
Pregnancy
Pregnancy Category C.
No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium
doses of up to 1.471 and 0.007 mg/kg/day. respectively. These doses correspond to approxi-
mately 660 and 6 times the recommended human daily dose (RHDD) on a mg/m2 basis.
However, in rats, fetal resorption, litter loss, decreases in the number of live pups at birth and
the mean pup weights, and a delay in pup sexual maturation were observed at inhalation
tiotropium doses of £0.078 mgftg (approximately 35 times the RHDD on a mg/m2 basis). In
rabbits, an increase in post-implantation loss was observed at an inhalation dose of
0.4 mg/kg/day (approximately 360 times the RHDD on a mg/m2 basis). Such effects were not
observed at inhalation doses of 0.009 and up to 0.088 mg/kg/day in rats and rabbits, respec-
tively. These doses correspond to approximately 4 and 80 times the RHDD on a mg/m2 basis,
respectively. These dose multiples may be over-estimated due to difficulties in measuring
deposited doses in animal inhalation studies.
There are no adequate and well-controlled studies in pregnant women. SPIRIVA HandiHaler
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Use in Labor and Delivery
The safety and effectiveness of SPIRIVA HandiHaler has not been studied during labor and
delivery.
Nursing Mothers
Clinical data from nursing women exposed to tiotropium are not available. Based on lactating
rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is
excreted in human milk, but because many drugs are excreted in human milk and given these
findings in rats, caution should be exercised if SPIRIVA HandiHaler is administered to a nurs-
ing woman.
Pediatric Use
SPIRIVA HandiHaler is approved for use in the maintenance treatment of bronchospasm asso-
ciated with chronic obstructive pulmonary disease, including chronic bronchitis and emphyse-
ma. This disease does not normally occur in children. The safety and effectiveness of SPIRI-
VA HandiHaler in pediatric patients have not been established.
Geriatric Use
Of the total number of patients who received SPIRIVA HandiHaler in the 1-year clinical trials,
426 were <65 years. 375 were 65-74 years and 105 were £75 years of age. Within each age
subgroup, there were no differences between the proportion of patients with adverse events in
the SPIRIVA HandiHaler and the comparator groups for most events. Dry mouth increased with
age in the SPIRIVA HandiHaler group (differences from placebo were 9.0%. 17.1%. and 16.2%
in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infec-
tions with increasing age was observed in the SPIRIVA HandiHaler group in the placebo-con-
trolled studies. The differences from placebo for constipation were 0%. 1.8%. and 7.8% for each
of the age groups. The differences from placebo for urinary tract infections were - 0.6%. 4.6%
and 4.5%. No overall differences in effectiveness were observed among these groups. Based on
available data, no adjustment of SPIRIVA HandiHaler dosage in geriatric patients is warranted.
ADVERSE REACTIONS
Of the 2.663 patients in the four
1
-year and two 6-month controlled clinical trials. 1,308 were treat-
ed with SPIRIVA HandiHaler at the recommended dose of 18 meg once a day. Patients with nar-
row angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were
excluded from these trials.
The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild
and often resolved dunng continued treatment. Other reactions reported in individual patients and
consistent with possible anticholinergic effects included constipation, increased heart rate, blurred
vision, glaucoma, urinary difficulty, and urinary retention.
Four mutticenter, 1 -year, controlled studies evaluated SPIRIVA HandiHaler in patients with COPD.
Table 1 shows all adverse events that occurred with a frequency of £3% in the SPIRIVA HandiHaler
group in the 1-year placebo-controlled trials where the rates in the SPIRIVA HandiHaler group
exceeded placebo by £1%.The frequency of corresponding events in the ipratropium-controlled tri-
als is included for comparison.
Table 1 Adverse Experience Incidence (% Patients) in One-Year-COPD Clinical Trials
Body System (Event)
Placebo-Controlled Trials
SPIRIVA
Placebo
[n = 550]
[n = 371]
Ipratropium-Controlled Trials
SPIRIVA
Ipratropium
[n = 356]
[n = 179]
Body as a Whole
Accidents
13
11
5
8
Chest Pain (non-specific)
7
5
5
2
Edema, Dependent
5
4
3
5
Gastrointestinal System Disorders
Abdominal Pain
5
3
6
6
Constipation
4
2
1
1
Dry Mouth
16
3
12
6
Dyspepsia
6
5
1
1
Vomiting
4
2
1
2
Musculoskeletal System
Myalgia
4
3
4
3
Resistance Mechanism Disorders
Infection
4
3
1
3
Moniliasis
4
2
3
2
Respiratory System (upper)
Epistaxis
4
2
1
1
Pharyngitis
9
7
7
3
Rhinitis
6
5
3
2
Sinusitis
11
9
3
2
Upper Respiratory
Tract Infection
41
37
43
35
Skin and Appendage Disorders
Rash
4
2
2
2
Urinary System
Urinary Tract Infection
7
5
4
2
Arthritis, coughing, and influenza-like symptoms occurred at a rate of £3% in the SPIRIVA
HandiHaler treatment group, but were <1% in excess of the placebo group.
Other events that occurred in the SPIRIVA HandiHaler group at a frequency of 1-3% in the
placebo-controlled trials where the rates exceeded that in the placebo group include:
Body as
a Whole:
allergic reaction, leg pain;
Central and Peripheral Nervous System:
dysphonia.
paresthesia;
Gastrointestinal System Disorders:
gastrointestinal disorder not otherwise speci-
fied (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis):
Metabolic and
Nutritional Disorders:
hypercholesterolemia, hyperglycemia:
Musculoskeletal System
Disorders:
skeletal pain:
Cardiac Events:
angina pectoris (including aggravated angina pec-
toris):
Psychiatric Disorder:
depression:
Infections:
herpes zoster;
Respiratory System
Disorder (Upper):
laryngitis;
Vision Disorder:
cataract. In addition, among the adverse events
observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular
tachycardia, angioedema. and urinary retention.
In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased
with age (see PRECAUTIONS, Geriatric Use).
Two multicenter. 6-month, controlled studies evaluated SPIRIVA HandiHaler in patients with
COPD. The adverse events and the incidence rates were similar to those seen in the 1 -year con-
trolled trials.
The following adverse reactions have been identified during worldwide post-approval use of
SPIRIVA HandiHaler: application site irritation (glossitis, mouth ulceration, and pharyngola-
ryngeal pain), dizziness, dysphagia, epistaxis. hoarseness, intestinal obstruction including
ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachy-
cardia. throat irritation, and urticaria.
DOSAGE AND ADMINISTRATION
SPIRIVA capsules must not be swallowed as the intended effects on the lungs will not
be obtained. The contents of the capsules are only for oral inhalation and should only
be used with the HandiHaler inhalation device (see OVERDOSAGE section).
The recommended dosage of SPIRIVA HandiHaler is the inhalation of the contents of one
SPIRIVA capsule, once-daily. with the HandiHaler inhalation device (see Patient’s
Instructions for Use).
No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired
patients. However, patients with moderate to severe renal impairment given SPIRIVA
HandiHaler
should
be
monitored
closely
(see
CLINICAL
PHARMACOLOGY,
Pharmacokinetics, Special Populations and PRECAUTIONS).
HOW SUPPLIED
The following packages are available:
carton containing 5 SPIRIVA capsules (1 unit-dose blister card) and
1 HandiHaler inhalation device (NDC 0597-0075-75)
carton containing 30 SPIRIVA capsules (3 unit-dose blister cards) and
1 HandiHaler inhalation device (NDC 0597-0075-41)
carton containing 90 SPIRIVA capsules (9 unit-dose blister cards) and
1 HandiHaler inhalation device (NDC 0597-0075-47)
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