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A SPIRIVA HandiHaler
(tintrnpiiim bromide inhalation powder)
Spiriva HandiHaler (tiotropium bromide inhalation powder)
FOR ORAL INHALATION ONLY
Brief Summary of Prescribing Information
INDICATIONS AND USAGE
SPIRIVA HandiHaler (tiotropium bromide inhalation powder) is indicated for the
long-term, once-daily. maintenance treatment of bronchospasm associated with
chronic obstructive pulmonary disease (COPD), including chronic bronchitis and
emphysema.
CONTRAINDICATIONS
SPIRIVA HandiHaler (tiotropium bromide inhalation powder) is contraindicated
in patients with a history of hypersensitivity to atropine or its derivatives, includ
ing ipratropium, or to any component of this product.
WARNINGS
SPIRIVA HandiHaler (tiotropium bromide inhalation powder) 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. If such a reaction occurs, therapy with SPIRIVA should be stopped at
once and alternative treatments should be considered. Inhaled medicines, includ
ing SPIRIVA. may cause paradoxical bronchospasm. If this occurs, treatment with
SPIRIVA should be stopped and other treatments considered.
PRECAUTIONS
General
As an anticholinergic drug. SPIRIVA (tiotropium bromide inhalation powder)
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 (creatinin
clearance of sSO mL-'min) treated with SPIRIVA should be monitored closely (see
CLINICAL PHARMACOLOGY. Pharmacokinetics, Special Populations. Renaliy
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. Capsules
should always be stored in sealed blisters. Remove only one capsule immedi
ately 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 immediately. 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 has been used concomitantly with other drugs commonly used in COPD
without increases in adverse drug reactions. These include sympathomimetic
bronchodilators. methylxanthines. and oral and inhaled steroids. However, the
co-administration of SPIRIVA with other anticholinergic-containing drugs (e.g..
'pratropium) 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 tiotropium 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/m 2
basis, respectively. These dose multiples may be over-estimated due to difficul
ties m measuring deposited doses in animal inhalation studies. Tiotropium bromide
demonstrated no evidence of mutagenicity or dastogemcity in the following
assays: the bacterial gene mutation assay, the V 79 Chinese hamster cell mutagen
esis assay, the chromosomal aberration assays in human lymphocytes in vitro and
mouse micronudeus formation 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 2 basis).
No such effects were observed at 0.009 mg/kg/day (approximately 4 times than
the RHDD on a mg/m 2 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/m‘ 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 approximately 660 and 6 times the recommended human daily dose
(RHDD) on a mg/m* 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 mg/kg
(approximately 35 times the RHDD on a mg/m* basis) In rabbits, an increase in post
implantation loss was observed at an inhalation dose of 0.4 mg/kg/day (approxi
mately 360 times the RHDD on a mg/m* basis). Such effects were not observed at
inhalation doses of 0.009 and up to 0.088 mg/kg/day in rats and rabbits, respectively.
These doses correspond to approximately 4 and 80 times the RHDD on a mg/m?
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 should be used during pregnan
cy only if the potential benefit justifies the potential risk to the fetus.
Use in Labor and Delivery
The safety and effectiveness of SPIRIVA has not been studied during labor and delivery.
Nursing Mothers
Clinical data from nursing women exposed to tiotropium are not available Based
on iactat-ng 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 is administered to a nursing woman.
Pediatric Use
SPIRIVA HandiHaler is approved for use in the maintenance treatment of broncho
spasm associated with chronic obstructive pulmonary disease, including chronic
bronchitis and emphysema. This disease does not normally occur in children. The
safety and effectiveness of SPIRIVA in pediatric patients have not been established
Geriatric Use
Of the total number of patients who received SPIRIVA 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. and the comparator groups for most
events. Dry mouth increased with age in the SPIRIVA 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 infections with increasing
age was observed in the SPIRIVA group In the placebo-controlled 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 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 treated with SPIRIVA (tiotropium bromide inhalation powder) at the
recommended dose of 18 meg once a day. Patients with narrow 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 during 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 multicenter. 1-year, controlled studies evaluat
ed SPIRIVA in patients with COPD. Table 1 shows all adverse events that occurred
with a frequency of *3% in the SPIRIVA group in the 1-year placebo-controlled trials
where the rates in the SPIRIVA group exceeded placebo by *l%. The frequenev of
corresponding events in the ipratropium-controlled trials is included for comparison.
Table 1: Adverse Experience Incidence (% Patients) in One-Year-COPD Clinical Trials
Body System (Event) Placebo-Controlled Trials Ipratropium-Controlled Trials
SPIRIVA Placebo SPIRIVA Ipratropium
[n « 550] [ns 371] [n»3s6] [n«l79]
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 l
Dry Mouth 16 3 12 6
Dyspepsia 6 5 1 l
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 treatment group, but were <l% in excess of the placebo group.
Other events that occurred in the SPIRIVA group at a frequency of 1-3% in the
placebo-controlled trials where the rates exceeded that in the placebo group include:
Body as o Whole: allergic reaction, leg pain: Central and Peripheral Nervous System:
dysphonia. paresthesia; Gastrointestinal System Disorders . gastrointestinal disorder
not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative
stomatitis): Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglyce
mia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris
(including aggravated angina pectoris); 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 <l% were atrial fibrillation, supraventricular tachycardia, angioedema.
and urinary retention. In the 1-year trials, the incidence of dry mouth, constipa
tion. and urinary tract infection increased with age (see PRECAUTIONS. Geriatric
Use). Two muiticenter, 6-month, controlled studies evaluated SPIRIVA in patients
with COPD. The adverse events and the incidence rates were similar to those seen in the
1-year controlled trials. The following adverse reactions have been identified during
worldwide post-approval use of SPIRIVA; dizziness, dysphagia, epistaxis. hoarseness,
intestinal obstruction including ileus paralytic, intraocular pressure increased, oral
candidiasis, palpitations, pruntus. tachycardia, throat irritation, and urticaria.
DOSAGE AND ADMINISTRATION
The recommended dosage of SPIRIVA HandiHaler (tiotropium bromide inhalation
powder) 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 adjust
ment is required for geriatric, hepatically-impaired. or renally-impaired patients.
However, patients with moderate to severe renal impairment given SPIRIVA should
be monitored closely (see CLINICAL PHARMACOLOGY. Pharmacokinetics, Special
Populations and PRECAUTIONS). SPIRIVA capsules are for inhalation only and
must not be swallowed.
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)
SV-BS (10-06)
65626/US/1
only
SPUOOO46B 5V44079
Copyright ©2007, Boehringer Ingelheim Pharmaceuticals. Inc. All rights reserved. (3/07)
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