Tiotropium Bromide
FDA Drug Information • Also known as: Spiriva Handihaler, Tiotropium Bromide
- Brand Names
- Spiriva Handihaler, Tiotropium Bromide
- Route
- ORAL, RESPIRATORY (INHALATION)
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Tiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules and a LupinHaler device. Each white opaque, hypromellose tiotropium bromide inhalation powder capsule contains a dry powder consisting of 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) blended with lactose monohydrate (which may contain milk proteins). The contents of tiotropium bromide inhalation powder capsules are intended for oral inhalation only, and are intended for administration only with the LupinHaler device. The active component of tiotropium bromide inhalation powder is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2β, 4β, 5α, 7β)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0 2,4 ] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is: Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C 19 H 22 NO 4 S 2 Br
What Is Tiotropium Bromide Used For?
1 INDICATIONS AND USAGE 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. Tiotropium bromide inhalation powder is indicated to reduce exacerbations in COPD patients. Tiotropium bromide inhalation powder is an anticholinergic indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION For oral inhalation only. Do not swallow tiotropium bromide inhalation powder capsules, as the intended effects on the lungs will not be obtained. The contents of the tiotropium bromide inhalation powder capsules should only be used with the LupinHaler ® device [see Overdosage ( 10 )] . The recommended dosage of tiotropium bromide inhalation powder is two inhalations of the powder contents of one tiotropium bromide inhalation powder capsule, once-daily, with the LupinHaler device [see Patient Counseling Information ( 17 )]. Do not take more than one dose in 24 hours. For administration of tiotropium bromide inhalation powder, a tiotropium bromide inhalation powder capsule is placed into the center chamber of the LupinHaler device. The tiotropium bromide inhalation powder capsule is pierced by pressing and releasing the green piercing button on the side of the LupinHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [see Patient Counseling Information ( 17 )]. No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given tiotropium bromide inhalation powder should be monitored closely for anticholinergic effects [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.5 , 8.6 , 8.7 ), and Clinical Pharmacology ( 12.3 )]. For oral inhalation only. DO NOT swallow tiotropium bromide inhalation powder capsules. Only use tiotropium bromide inhalation powder capsules with the LupinHaler ® device ( 2 ) Two inhalations of the powder contents of a single tiotropium bromide inhalation powder capsule (18 mcg) once daily ( 2 )
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Immediate hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] Paradoxical bronchospasm [see Warnings and Precautions ( 5.3 )] Worsening of narrow-angle glaucoma [see Warnings and Precautions ( 5.4 )] Worsening of urinary retention [see Warnings and Precautions ( 5.5 )] The most common adverse reactions (>5% incidence in the 1-year placebo- controlled trials) were upper respiratory tract infection, dry mouth, sinusitis, pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, and rhinitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice. 6-Month to 1-Year Trials The data described below reflect exposure to tiotropium bromide inhalation powder in 2,663 patients. Tiotropium bromide inhalation powder 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, 1,308 patients were treated with tiotropium bromide inhalation powder at the recommended dosage 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 (FEV 1 ) 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 tiotropium bromide inhalation powder in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the tiotropium bromide inhalation powder group in the 1-year placebo-controlled trials where the rates in the tiotropium bromide inhalation powder group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison. Table 1: Adverse Reactions (% Patients) in One-Year COPD Clinical Trials Body System (Event) Placebo-Controlled Trials Ipratropium-Controlled Trials Tiotropium Bromide Inhalation Powder (n = 550) Placebo (n = 371) Tiotropium Bromide Inhalation Powder (n = 356) Ipratropium (n = 179) Body as a Whole Chest Pain (non-specific) 7 5 5 2 Edema, Dependent 5 4 3 5 Gastrointestinal System Disorders Dry Mouth 16 3 12 6 Dyspepsia 6 5 1 1 Abdominal Pain 5 3 6 6 Constipation 4 2 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) Upper Respiratory Tract Infection 41 37 43 35 Sinusitis 11 9 3 2 Pharyngitis 9 7 7 3 Rhinitis 6 5 3 2 Epistaxis 4 2 1 1 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 tiotropium bromide inhalation powder treatment group, but were <1% in excess of the placebo group. Other reactions that occurred in the...
Drug Interactions
7 DRUG INTERACTIONS Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of tiotropium bromide inhalation powder with other anticholinergic-containing drugs. ( 7.2 ) 7.1 Sympathomimetics, Methylxanthines, Steroids Tiotropium bromide inhalation powder has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse reactions. 7.2 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of tiotropium bromide inhalation powder with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions ( 5.4 , 5.5 ) and Adverse Reactions ( 6 )].
Contraindications
4 CONTRAINDICATIONS Tiotropium bromide inhalation powder is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product [see Warnings and Precautions ( 5.2 )] . In clinical trials and postmarketing experience with tiotropium bromide inhalation powder, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported [see Warnings and Precautions ( 5.2 )] . Hypersensitivity to tiotropium, ipratropium, or any components of tiotropium bromide inhalation powder capsules ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary The limited human data with tiotropium bromide inhalation powder use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. Based on animal reproduction studies, no structural abnormalities were observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the period of organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID). Increased post-implantation loss was observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately 790 and 8 times the MRHDID, respectively (on a mcg/m 2 basis at inhalation doses of 1,471 and 7 mcg/kg/day in rats and rabbits, respectively). No evidence of structural abnormalities was observed in rats or rabbits. However, in rats, tiotropium caused 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 at tiotropium doses of approximately 40 times the MRHDID (on a mcg/m 2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at a tiotropium dose of approximately 430 times the MRHDID (on a mcg/m 2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95...
Overdosage
10 OVERDOSAGE High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once- daily inhalation of 141 mcg of tiotropium. Treatment of overdosage consists of discontinuation of tiotropium bromide inhalation powder together with institution of appropriate symptomatic and/or supportive therapy. Accidental Ingestion Acute intoxication by inadvertent oral ingestion of tiotropium bromide inhalation powder capsules is unlikely since it is not well-absorbed systemically. A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, tiotropium bromide inhalation powder was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Tiotropium bromide inhalation powder consists of tiotropium bromide inhalation powder capsules and the LupinHaler device. Tiotropium bromide inhalation powder capsules contain 18 mcg of tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate USP) in a hypromellose capsule with white opaque cap and white opaque body, imprinted with "LU" on cap and "T18" on body. The LupinHaler device is a white colour inhaler with a green piercing button. It is also imprinted with LupinHaler, Tiotropium Bromide Inhalation Powder and the LUPIN company Logo. It is also imprinted to indicate that Tiotropium Bromide Inhalation Powder Capsules should not be stored in the LupinHaler device and that the LupinHaler device is only to be used with Tiotropium Bromide Inhalation Powder Capsules. Tiotropium bromide inhalation powder capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. Tiotropium bromide inhalation powder capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual tiotropium bromide inhalation powder capsule is opened. The following packages are available: carton (NDC 68180-964-12) containing 30 Tiotropium Bromide Inhalation Powder Capsules (3 unit-dose blister cards NDC 68180-964-11) and 1 LupinHaler inhalation device Keep out of reach of children. Do not get powder into eyes. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. The Tiotropium Bromide Inhalation Powder Capsules should not be exposed to extreme temperature or moisture. Do not store Tiotropium Bromide Inhalation Powder Capsules in the LupinHaler device.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.