TROPIRUS

Tiotropium is a long-acting, antimuscarinic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD) and asthma. 1, 2, 3, 4, 5 Tiotropium acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation and bronchodilation. 1, 2, 3, 4, 5 Tiotropium is more specific for the subset of muscarinic receptors commonly found in the lungs than ipratropium.

Tiotropium was granted

FDA approval on 30 January 2004.

Tiotropium powder for inhalation is indicated for the maintenance of bronchospasm in COPD and to prevent exacerbations of COPD.

A combination tiotropium and olodaterol metered inhalation spray is indicated for maintenance of COPD.

A tiotropium inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 12 or more years old.

A tiotropium metered inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 6 or more years old.

Tiotropium is a long acting antimuscarinic that causes bronchodilation. 1, 2, 3, 4, 5 The effects of tiotropium last over 24 hours and there is a wide therapeutic index as overdoses are uncommon even at doses well above the recommended maximum. 2, 3, 4, 5.

33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. 1, 3, 4, 5 A dry powder for inhalation is 19.5% bioavailable. 1, 2 Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 minutes. 3, 4, 5.

The volume of distribution of tiotropium is 32 L/kg. 1, 2, 3, 4, 5.

Tiotropium is not heavily metabolized in the body. 2, 3, 4, 5 74% of an intravenous dose is excreted in the urine as unchanged drug. 2, 3, 4, 5 Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. 2, 3, 4, 5 In vitro experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites. 2, 3, 4, 5 Hover over products below to view reaction partners Tiotropium Dithienylglycolic Acid + N-methylscopine.

74% of intravenous tiotropium was excreted unchanged in urine. 1, 2, 3, 4, 5 14% of a dry powder inhalation dose was excreted unchanged in the urine. 1 24 hour urinary excretion after 21 days of 5 µg once daily inhalation in patients with COPD is 18.6% and in patients with asthma is 12.8%. 2, 3, 4, 5.

The terminal half life of tiotropium is 24 hours in patients with COPD and 44 hours in patients with asthma. 4, 5.

The total clearance of tiotropium is 880 mL/min in healthy subjects receiving 5 µg daily. 1, 2 The renal clearance of tiotropium was 669 mL/min.

Patients <65 years old demonstrated a clearance of 365 mL/min while patients ≥65 demonstrated a clearance of 271 mL/min.

This decreased clearance is not associated with increased AUC or C max. 3, 4, 5.

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Symptoms of overdose include altered mental status, tremors, abdominal pain, and severe constipation.

However, doses of up to 282 µg did not lead to systemic anticholinergic effects in a trial of 6 patients. 3, 4, 5 In case of overdose, stop tiotropium and being symptomatic and supportive therapy. 2, 3, 4, 5.

Use of a

LABA, including STIOLTO RESPIMAT, without an inhaled corticosteroid is contraindicated in patients with asthma.

RESPIMAT is not indicated for the treatment of asthma.

RESPIMAT is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product.

In clinical trials and postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.

Hypersensitivity reactions were also reported in clinical trials with STIOLTO RESPIMAT.

Hypersensitivity to tiotropium, ipratropium, olodaterol, or any component of this product.

For oral inhalation only.

Two inhalations of STIOLTO

RESPIMAT once-daily at the same time of day. 2.1 Recommended Dosage The recommended dosage of STIOLTO RESPIMAT is two inhalations once-daily at the same time of the day. Do not use STIOLTO RESPIMAT more than two inhalations every 24 hours. 2.2 Administration Information For oral inhalation only.

Prior to first use, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and the unit is primed.

When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times.

The unit is then considered primed and ready for use.

If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use.

If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients.

However, patients with moderate to severe renal impairment given STIOLTO RESPIMAT should be monitored closely for anticholinergic effects.

Inhalation Spray is supplied in a labeled carton containing one STIOLTO RESPIMAT cartridge and one STIOLTO RESPIMAT inhaler.

RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap.

The STIOLTO RESPIMAT cartridge is only intended for use with the STIOLTO RESPIMAT inhaler and should not be interchanged with any other RESPIMAT device delivered product.

RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base.

The clear base is removed to insert the cartridge.

The inhaler contains a dose indicator.

The light green-colored cap and the written information on the label of the gray inhaler body indicate that it is labeled for use with the STIOLTO RESPIMAT cartridge.

STIOLTO RESPIMAT Inhalation Spray is available as: STIOLTO RESPIMAT Inhalation Spray: 60 metered actuations (NDC 0597-0155-61) STIOLTO RESPIMAT Inhalation Spray: 10 metered actuations (NDC 0597-0155-70) (institutional pack) The STIOLTO RESPIMAT cartridge has a net fill weight of at least 4 grams and when used with the STIOLTO RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations after preparation for use.

When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.

After assembly, the STIOLTO RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.

Keep out of reach of children.

Do not spray into eyes.

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) .

Avoid freezing.

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) .

Avoid freezing.

There are no adequate and well-controlled clinical studies with STIOLTO RESPIMAT or its individual components, tiotropium bromide and olodaterol, in pregnant women to inform of drug-associated risk of adverse pregnancy-related outcomes.

Animal reproduction studies were conducted with the individual components of STIOLTO RESPIMAT, tiotropium bromide and olodaterol.

There are clinical considerations with the use of STIOLTO RESPIMAT in pregnant women.

RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 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.

Based on animal studies, olodaterol was not teratogenic when administered to pregnant rats or rabbits during organogenesis at inhalation doses of approximately 2,731 or 1,353 times the MRHDID (on an AUC basis), in rats or rabbits, respectively.

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.

There are no adequate and well-controlled human studies that have investigated the effects of STIOLTO RESPIMAT on preterm labor or labor at term.

Because of the potential for beta-agonist interference with uterine contractility, use of STIOLTO RESPIMAT during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Animal reproduction studies with the combination of tiotropium and olodaterol are not available; however, studies are available with the individual components.

In 2 separate embryo-fetal development studies, pregnant rats and rabbits received tiotropium during the period of organogenesis at doses up to approximately and 8 times the MRHDID, respectively (on a mcg/m 2 basis at inhalation doses of 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 and 95 times the MRHDID, respectively (on a mcg/m 2 basis at inhalation doses of and 88 mcg/kg/day in rats and rabbits, respectively).

Olodaterol was not teratogenic in rats at inhalation doses approximately 2,731 times the MRHDID (on an AUC basis at a maternal inhalation dose of 1,054 mcg/kg/day).

No significant effects occurred in rabbits at inhalation doses approximately 1,353 times the MRHDID in adults (on an AUC basis at a maternal inhalation dose of 974 mcg/kg/day).

Placental transfer of olodaterol was observed in pregnant rats.

Olodaterol has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHDID in adults (on an AUC basis at a maternal inhalation dose of 2,489 mcg/kg/day).

Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum.

COPD does not normally occur in children.

The safety and effectiveness of STIOLTO

RESPIMAT in the pediatric population has not been established.

Based on available data, no adjustment of STIOLTO RESPIMAT dosage in geriatric patients is warranted.

Of the 1,029 patients who received STIOLTO RESPIMAT at the recommended dose once daily in the clinical studies from the pooled 1-year database, 525 (51.0%) were <65 years of age, 407 (39.6%) were to <75, 96 (9.3%) were to <85, and 1 (0.1%) was ≥85.

No overall differences in effectiveness were observed, and in the 1-year pooled data, the adverse drug reaction profiles were similar in the older population compared to the patient population overall.