SPIRIVA 18 MCG Inhalant Powder Capsule
Generic Name: TIOTROPIUM BROMIDE MONOHYDRATE
Brand Name: Spiriva
- Substance Name(s):
- TIOTROPIUM BROMIDE MONOHYDRATE
DRUG INTERACTIONS
7 Not recommended for use with other anticholinergics since this has not been studied (7.2) 7.1 Sympathomimetics, Methylxanthines, Steroids SPIRIVA HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions. 7.2 Anticholinergics The co-administration of SPIRIVA HandiHaler with other anticholinergic-containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. 7.3 Cimetidine, Ranitidine No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine [ see Clinical Pharmacology (12.3) ].
OVERDOSAGE
10 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. Accidental Ingestion Acute intoxication by inadvertent oral ingestion of SPIRIVA 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, SPIRIVA HandiHaler was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day. No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300, 120,000, and 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
DESCRIPTION
11 SPIRIVA HandiHaler consists of a capsule dosage form containing a dry powder formulation of tiotropium intended for oral inhalation only with the HandiHaler device. Each light green, hard gelatin SPIRIVA capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins) as the carrier. The dry powder formulation within the SPIRIVA capsule is intended for oral inhalation only. The active component of SPIRIVA HandiHaler is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]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 C19H22NO4S2Br • H2O. The HandiHaler device is an inhalation device used to inhale the dry powder contained in the SPIRIVA capsule. The dry powder is delivered from the HandiHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HandiHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HandiHaler device, which may vary from patient to patient, and may vary with the exposure time of the SPIRIVA capsule outside the blister pack. SPIRIVA Structure
CLINICAL STUDIES
6.1 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 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 SPIRIVA (n = 550) Placebo (n = 371) SPIRIVA (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 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 (8.5) ]. 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.
HOW SUPPLIED
16 /STORAGE AND HANDLING SPIRIVA HandiHaler consists of SPIRIVA capsules and the HandiHaler device. SPIRIVA capsules contain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheim company logo on the SPIRIVA capsule cap and TI 01 on the SPIRIVA capsule body, or vice versa. The HandiHaler device is gray colored with a green piercing button. It is imprinted with SPIRIVA HandiHaler (tiotropium bromide inhalation powder), the Boehringer Ingelheim company logo, and the Pfizer company logo. It is also imprinted to indicate that SPIRIVA capsules should not be stored in the HandiHaler device and that the HandiHaler device is only to be used with SPIRIVA capsules. SPIRIVA capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. SPIRIVA 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 SPIRIVA capsule is opened. The following packages are available: carton containing 6 SPIRIVA capsules (5 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 54868-5109-0) carton containing 90 SPIRIVA capsules (9 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 54868-5109-1) Storage Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. The SPIRIVA capsules should not be exposed to extreme temperature or moisture. Do not store SPIRIVA capsules in the HandiHaler device.
RECENT MAJOR CHANGES
Indications and Usage (1) 12/2009 Dosage and Administration (2) 12/2009 Contraindications (4) 12/2009 Warnings and Precautions, Immediate Hypersensitivity Reactions (5.2) 12/2009 Worsening of Narrow-Angle Glaucoma (5.4) 12/2009 Worsening of Urinary Retention (5.5) 12/2009 Renal Impairment (5.6) 12/2009
GERIATRIC USE
8.5 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 to 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 infections with increasing age was observed in the SPIRIVA HandiHaler 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 HandiHaler dosage in geriatric patients is warranted [ see Clinical Pharmacology (12.3) ].
DOSAGE FORMS AND STRENGTHS
3 SPIRIVA HandiHaler consists of SPIRIVA capsules and a HandiHaler device. SPIRIVA capsules contain 18 mcg dry powder formulation of tiotropium in a light green, hard gelatin capsule with TI 01 printed on one side and Boehringer Ingelheim company logo on the other side. Supplied with a HandiHaler device. SPIRIVA capsules for oral inhalation: 18 mcg tiotropium powder, for use with HandiHaler device (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.
INDICATIONS AND USAGE
1 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. SPIRIVA HandiHaler is indicated to reduce exacerbations in COPD patients. SPIRIVA HandiHaler 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)
PEDIATRIC USE
8.4 Pediatric Use SPIRIVA HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and effectiveness of SPIRIVA HandiHaler in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Teratogenic Effects, Pregnancy Category C. 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. No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660 and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. 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 inhalation tiotropium doses of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis. Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.
NUSRING MOTHERS
8.3 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 nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Not for acute use: Not for use as a rescue medication (5.1) Immediate hypersensitivity reactions: Discontinue SPIRIVA HandiHaler at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, occur. Use with caution in patients with severe hypersensitivity to milk proteins. (5.2) Paradoxical bronchospasm: Discontinue SPIRIVA HandiHaler and consider other treatments if paradoxical bronchospasm occurs (5.3) Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.4) Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. (5.5) 5.1 Not for Acute Use 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). 5.2 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash 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. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to SPIRIVA HandiHaler. In addition, SPIRIVA HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins. 5.3 Paradoxical Bronchospasm Inhaled medicines, including SPIRIVA HandiHaler, may cause paradoxical bronchospasm. If this occurs, treatment with SPIRIVA HandiHaler should be stopped and other treatments considered. 5.4 Worsening of Narrow-Angle Glaucoma SPIRIVA HandiHaler should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.5 Worsening of Urinary Retention SPIRIVA HandiHaler should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.6 Renal Impairment As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with SPIRIVA HandiHaler should be monitored closely for anticholinergic side effects [ see Clinical Pharmacology (12.3) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (17.6) 17.1 Instructions for Administering SPIRIVA HandiHaler It is important for patients to understand how to correctly administer SPIRIVA capsules using the HandiHaler device [ see Patient Counseling Information (17.6) ]. Patients should be instructed that 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 . SPIRIVA capsules should always be stored in sealed blisters. Only one SPIRIVA capsule should be removed immediately before use or its effectiveness may be reduced. Additional SPIRIVA capsules that are exposed to air (i.e., not intended for immediate use) should be discarded. 17.2 Paradoxical Bronchospasm Patients should be informed that SPIRIVA HandiHaler can produce paradoxical bronchospasm. If paradoxical bronchospasm occurs, patients should discontinue SPIRIVA HandiHaler. 17.3 Urinary Retention Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop. 17.4 Visual Effects 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. Patients should be told to consult a physician immediately should any of these signs and symptoms develop. Miotic eye drops alone are not considered to be effective treatment. Patients should be told that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation. 17.5 Acute Exacerbation Patients should understand that 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). 17.6 FDA-approved Patient Labeling Patient Information and Patient’s Instructions for Use are supplied as tear-off leaflets following the full prescribing information and should be dispensed with each new prescription and refill. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Pfizer Inc New York, NY 10017 USA Licensed from: Boehringer Ingelheim International GmbH Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY. SPIRIVA® and HandiHaler® are registered trademarks and are used under license from Boehringer Ingelheim International GmbH. ©Copyright 2009 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED SPIRIVA® (tiotropium bromide inhalation powder) is covered by U.S. Patent Nos. RE38,912, RE39,820, 5,478,578, 6,777,423, 6,908,928, 7,070,800, and 7,309,707 with other patents pending. The HandiHaler® inhalation device is covered by U.S. Design Patent No. D355,029 with other patents pending. Rev: December 2009 IT1600WL1609 10004551/07 65626-08 Relabeling of “Additional Barcode” by: Physicians Total Care, Inc. Tulsa, OK 74146
DOSAGE AND ADMINISTRATION
2 DO NOT SWALLOW SPIRIVA CAPSULES FOR USE WITH HANDIHALER DEVICE ONLY FOR ORAL INHALATION ONLY SPIRIVA capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of the SPIRIVA capsules are only for oral inhalation and should only be used with the HandiHaler device [ see Overdosage (10) ]. The recommended dose of SPIRIVA HandiHaler is two inhalations of the powder contents of one SPIRIVA capsule, once-daily, with the HandiHaler device [ see Patient Counseling Information (17.6) ]. For administration of SPIRIVA HandiHaler, a SPIRIVA capsule is placed into the center chamber of the HandiHaler device. The SPIRIVA capsule is pierced by pressing and releasing the green piercing button on the side of the HandiHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [ see Patient Counseling Information (17.6) ]. 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 for anticholinergic effects [ see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3) ]. DO NOT swallow SPIRIVA capsules (2) For Use with the HandiHaler Device ONLY (2) For Oral Inhalation ONLY (2) Two inhalations of the powder contents of a single SPIRIVA capsule (18 mcg) once daily (2)