Tiotropium-nativ

Tiotropium-nativ 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. Tiotropium-nativ HANDIHALER is indicated to reduce exacerbations in COPD patients.

For oral inhalation only. Do not swallow Tiotropium-nativ capsules, as the intended effects on the lungs will not be obtained. The contents of the Tiotropium-nativ capsules should only be used with the HANDIHALER device

The recommended dose of Tiotropium-nativ HANDIHALER is two inhalations of the powder contents of one Tiotropium-nativ capsule, once-daily, with the HANDIHALER device. Do not take more than one dose in 24 hours.

For administration of Tiotropium-nativ HANDIHALER, a Tiotropium-nativ capsule is placed into the center chamber of the HANDIHALER device. The Tiotropium-nativ 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

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given Tiotropium-nativ HANDIHALER should be monitored closely for anticholinergic effects.

Tiotropium-nativ HANDIHALER is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product. In clinical trials and postmarketing experience with Tiotropium-nativ HANDIHALER, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Not For Acute Use

Tiotropium-nativ HANDIHALER is intended as a once-daily maintenance treatment for COPD and should not be used for relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administration of Tiotropium-nativ HANDIHALER. If such a reaction occurs, therapy with Tiotropium-nativ 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 or its derivatives should be closely monitored for similar hypersensitivity reactions to Tiotropium-nativ HANDIHALER. In addition, Tiotropium-nativ HANDIHALER should be used with caution in patients with severe hypersensitivity to milk proteins.

Paradoxical Bronchospasm

Inhaled medicines, including Tiotropium-nativ HANDIHALER, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled shortacting beta2-agonist such as albuterol. Treatment with Tiotropium-nativ HANDIHALER should be stopped and other treatments considered.

Worsening Of Narrow-Angle Glaucoma

Tiotropium-nativ 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.

Worsening Of Urinary Retention

Tiotropium-nativ HANDIHALER should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Renal Impairment

As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Tiotropium-nativ HANDIHALER should be monitored closely for anticholinergic side effects.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Paradoxical Bronchospasm

Inform patients that Tiotropium-nativ HANDIHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Tiotropium-nativ HANDIHALER.

Worsening of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of 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 and symptoms develop.

Inform patients 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.

Since dizziness and blurred vision may occur with the use of Tiotropium-nativ HANDIHALER, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.

Worsening of Urinary Retention

Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Not for Acute Use

Instruct patients that Tiotropium-nativ HANDIHALER is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

Instructions for Administering Tiotropium-nativ HANDIHALER

Instruct patients on how to correctly administer Tiotropium-nativ capsules using the HANDIHALER device. Instruct patients that Tiotropium-nativ capsules should only be administered via the HANDIHALER device and the HANDIHALER device should not be used for administering other medications. Remind patients that the contents of Tiotropium-nativ capsules are for oral inhalation only and must not be swallowed.

Instruct patients always to store Tiotropium-nativ capsules in sealed blisters and to remove only one Tiotropium-nativ capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional Tiotropium-nativ capsules that are exposed to air (i.e., not intended for immediate use).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0.5 times the recommended human daily inhalation dose (MRHDID) on a mcg/m² basis, respectively.

Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity 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 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 78 mcg/kg/day or greater (approximately 40 times the MRHDID on a mcg/m² basis). No such effects were observed at 9 mcg/kg/day (approximately 5 times the MRHDID on a mcg/m² basis). The fertility index, however, was not affected at inhalation doses up to 1689 mcg/kg/day (approximately 910 times the MRHDID on a mcg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Tiotropium-nativ 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 approximately 790 and 8 times the maximum recommended human daily inhalation dose (MRHDID), respectively (on a mcg/m² basis at maternal inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, 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 40 times the MRHDID (on a mcg/m² basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in postimplantation loss at an inhalation dose of approximately 430 times the MRHDID (on a mcg/m² basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at inhalation doses of approximately 5 and 95 times the MRHDID, respectively (on a mcg/m² basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

Labor And Delivery

The safety and effectiveness of Tiotropium-nativ 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 Tiotropium-nativ HANDIHALER is administered to a nursing woman.

Pediatric Use

Tiotropium-nativ HANDIHALER is not indicated for use in children. The safety and effectiveness of Tiotropium-nativ HANDIHALER in pediatric patients have not been established.

Geriatric Use

Based on available data, no adjustment of Tiotropium-nativ HANDIHALER dosage in geriatric patients is warranted.

Of the total number of patients who received Tiotropium-nativ 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 Tiotropium-nativ HANDIHALER and the comparator groups for most events. Dry mouth increased with age in the Tiotropium-nativ 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 Tiotropium-nativ 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.

Renal Impairment

Patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Tiotropium-nativ HANDIHALER should be monitored closely for anticholinergic side effects.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

The following adverse reactions are described, or described in greater detail, in other sections:

• Immediate hypersensitivity reactions
• Paradoxical bronchospasm
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention

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-nativ HANDIHALER in 2663 patients. Tiotropium-nativ 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 Tiotropium-nativ 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 Tiotropium-nativ HANDIHALER in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥ 3% in the Tiotropium-nativ HANDIHALER group in the 1-year placebo-controlled trials where the rates in the Tiotropium-nativ 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

Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥ 3% in the Tiotropium-nativ HANDIHALER treatment group, but were < 1% in excess of the placebo group.

Other reactions that occurred in the Tiotropium-nativ 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.

Two multicenter, 6-month, controlled studies evaluated Tiotropium-nativ 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 Tiotropium-nativ HANDIHALER in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Tiotropium-nativ 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 Tiotropium-nativ HANDIHALER group where the rates in the Tiotropium-nativ HANDIHALER group exceeded placebo by ≥ 1%, adverse reactions included (Tiotropium-nativ 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 Tiotropium-nativ 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 Tiotropium-nativ 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.

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 oncedaily inhalation of 141 mcg of tiotropium.

Treatment of overdosage consists of discontinuation of Tiotropium-nativ HANDIHALER together with institution of appropriate symptomatic and/or supportive therapy.

Accidental Ingestion

Acute intoxication by inadvertent oral ingestion of Tiotropium-nativ 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-nativ HANDIHALER was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day.

Cardiac Electrophysiology

In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec was higher in the Tiotropium-nativ HANDIHALER group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of > 500 msec. Other clinical studies with Tiotropium-nativ HANDIHALER did not detect an effect of the drug on QTc intervals.

The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium dry powder for inhalation 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium dry powder for inhalation 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc > 500 msec or QTc changes from baseline of ≥ 60 msec.

Tiotropium is administered by dry powder inhalation. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy. A dedicated pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the RESPIMAT inhaler (5 mcg) and as inhalation powder (18 mcg) from the HANDIHALER device resulted in a similar systemic exposure between the two products.

Absorption

Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Oral solutions of tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of tiotropium. Maximum tiotropium plasma concentrations were observed 7 minutes after inhalation.

Distribution

Tiotropium is 72% bound to plasma protein and had a volume of distribution of 32 L/kg after intravenous administration to young healthy volunteers. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not readily penetrate the blood-brain barrier.

Elimination

The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was 880 mL/min after intravenous administration in young healthy volunteers. After chronic once-daily dry powder inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Metabolism

The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which binds to muscarinic receptors.

In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

Excretion

Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After dry powder inhalation to COPD patients at steady state, urinary excretion was 7% (1.3 μg) of the unchanged dose over 24 hours. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine.