The following adverse reactions are described, or described in greater detail, in other sections:
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Immediate hypersensitivity reactions [see Warnings and Precautions]
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Paradoxical bronchospasm [see Warnings and Precautions]
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Worsening of narrow-angle glaucoma [see Warnings and Precautions]
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Worsening of urinary retention [see Warnings and Precautions]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
6-Month to 1-Year Trials
The data described below reflect exposure to SPIRIVA HandiHaler in 2663 patients. SPIRIVA HandiHaler
was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month
placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with SPIRIVA
HandiHaler at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87
years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory
volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or
symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.
An additional 6-month trial conducted in a Veteran's Affairs setting is not included in this safety database
because only serious adverse events were collected.
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, tachycardia, blurred vision, glaucoma (new onset or worsening),
dysuria, and urinary retention.
Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated SPIRIVA HandiHaler in patients
with COPD. Table 1 shows all adverse reactions 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 reactions in the ipratropium-controlled trails is included for comparison.
Table 1 Adverse Reactions (% Patients) in One-Year COPD Clinical Trials
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 reactions that occurred in the SPIRIVA HandiHaler group at a frequency of 1% to 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 specified (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 pectoris); Psychiatric Disorder:
depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis;
Vision Disorder: cataract. In addition, among the adverse reactions 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 Use in Specific Populations].
Two multicenter, 6-month, controlled studies evaluated SPIRIVA HandiHaler in patients with COPD. The
adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials.
4-Year Trial
The data described below reflect exposure to SPIRIVA HandiHaler in 5992 COPD patients in a 4-year
placebo-controlled trial. In this trial, 2986 patients were treated with SPIRIVA HandiHaler at the
recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was
75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted
of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet
obstruction were excluded from these trials. When the adverse reactions were analyzed with a
frequency of ≥3% in the SPIRIVA HandiHaler group where the rates in the SPIRIVA HandiHaler group
exceeded placebo by ≥1%, adverse reactions included (SPIRIVA HandiHaler, placebo): pharyngitis
(12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%),
dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%).
Additional Adverse Reactions
Other adverse reactions not previously listed that were reported more frequently in COPD patients
treated with SPIRIVA HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis,
oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.
Postmarketing Experience
Adverse reactions have been identified during worldwide post-approval use of SPIRIVA HandiHaler.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure. These adverse reactions are: application site irritation (glossitis, mouth ulceration,
and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction including ileus
paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia,
throat irritation, and urticaria.