Тиотропия бромида моногидрад

Erhaltungstherapie chronisch obstruktiver Lungenerkrankungen

Тиотропия бромида моногидрад (Tiotropiumbromid) ist für die langfristige, einmal tägliche Erhaltungsbehandlung von Bronchospasmus im Zusammenhang mit chronisch obstruktiven Lungenerkrankungen (COPD), einschließlich chronischer Bronchitis und Emphysem, angezeigt. Тиотропия бромида моногидрад ist angezeigt, um Exazerbationen bei COPD-Patienten zu reduzieren.

Wichtige Nutzungsbeschränkung

Тиотропия бромида моногидрад ist NICHT zur Linderung von akutem Bronchospasmus indiziert.

Erhaltungstherapie von Asthma

Тиотропия бромида моногидрад ist ein Bronchodilatator, der für die langfristige, einmal tägliche Erhaltungstherapie von Asthma bei Patienten ab 6 Jahren angezeigt ist.

Wichtige Nutzungsbeschränkung

Тиотропия бромида моногидрад ist NICHT zur Linderung von akutem Bronchospasmus indiziert.

Тиотропия бромида моногидрад HANDIHALER (Tiotropiumbromid-Inhalationspulver) ist für die langfristige, einmal tägliche Erhaltungstherapie von Bronchospasmus im Zusammenhang mit chronisch obstruktiven Lungenerkrankungen (COPD), einschließlich chronischer Bronchitis und Emphysem, indiziert. Тиотропия бромида моногидрад HANDIHALER ist angezeigt, um Exazerbationen bei COPD-Patienten zu reduzieren.

Um die volle Dosis der Medikamente zu erhalten, muss Тиотропия бромида моногидрад einmal täglich als zwei Inhalationen verabreicht werden. Nehmen Sie nicht mehr als eine Dosis (2 Inhalationen) innerhalb von 24 Stunden ein.

Vor der ersten Verwendung wird die SPIRIVA RESPIMAT-Patrone in den Тиотропия бромида моногидрад-Inhalator eingefügt und das Gerät vorbereitet. Bei der ersten Verwendung des Geräts müssen die Patienten den Inhalator in Richtung Boden betätigen, bis eine Aerosolwolke sichtbar ist, und den Vorgang dann noch dreimal wiederholen. Das Gerät gilt dann als vorbereitet und gebrauchsfertig. Bei länger als 3 Tagen nicht angewendet, müssen die Patienten den Inhalator einmal betätigen, um den Inhalator für die Anwendung vorzubereiten. Wenn die Patienten länger als 21 Tage nicht angewendet werden, müssen sie den Inhalator betätigen, bis eine Aerosolwolke sichtbar ist, und den Vorgang dann noch dreimal wiederholen, um den Inhalator für die Verwendung vorzubereiten.

Chronisch obstruktive Lungenerkrankung

Die empfohlene Dosierung für Patienten mit COPD beträgt 2 Inhalationen von Тиотропия бромида моногидрад 2,5 µg pro Betätigung einmal täglich; Die Gesamtdosis beträgt 5 µg Тиотропия бромида моногидрад.

Asthma

Die empfohlene Dosierung für Patienten mit Asthma beträgt 2 Inhalationen von Тиотропия бромида моногидрад 1,25 µg pro Betätigung einmal täglich; Die Gesamtdosis beträgt 2,5 µg Тиотропия бромида моногидрад. Bei der Behandlung von Asthma kann der maximale Nutzen der Lungenfunktion bis zu 4 bis 8 Wochen nach der Dosierung betragen.

Spezielle Populationen

Bei geriatrischen, hepatisch beeinträchtigten oder renal beeinträchtigten Patienten ist keine Dosisanpassung erforderlich. Patienten mit mittelschwerer bis schwerer Nierenfunktionsstörung, denen SPIRIVA RESPIMAT verabreicht wurde, sollten jedoch engmaschig auf anticholinerge Wirkungen überwacht werden.

Nur zum oralen Einatmen. Schlucken Sie keine Тиотропия бромида моногидрад-Kapseln, da die beabsichtigten Auswirkungen auf die Lunge nicht erhalten werden. Der Inhalt der Тиотропия бромида моногидрад-Kapseln sollte nur mit dem HANDIHALER-Gerät verwendet werden

Die empfohlene Dosis von Тиотропия бромида моногидрад HANDIHALER ist zwei Einatmen des Pulverinhalts einer Тиотропия бромида моногидрад Kapsel, einmal täglich, mit dem HANDIHALER-Gerät. Nehmen Sie nicht mehr als eine Dosis in 24 Stunden ein.

Für die Verabreichung von Тиотропия бромида моногидрад HANDIHALER wird eine Тиотропия бромида моногидрад Kapsel in die Mittelkammer des HANDIHALER-Geräts gelegt. Die Kapsel Тиотропия бромида моногидрад wird durch Drücken und Loslassen des grünen Piercing-Knopfs an der Seite des HANDIHALER-Geräts durchbohrt. Die Tiotropiumformulierung wird beim Einatmen des Patienten durch das Mundstück in den Luftstrom dispergiert

Bei geriatrischen, hepatisch beeinträchtigten oder renal beeinträchtigten Patienten ist keine Dosisanpassung erforderlich. Patienten mit mittelschwerer bis schwerer Nierenfunktionsstörung, denen Тиотропия бромида моногидрад HANDIHALER verabreicht wurde, sollten jedoch engmaschig auf anticholinerge Wirkungen überwacht werden.

Тиотропия бромида моногидрад is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any component of this product. In clinical trials with Тиотропия бромида моногидрад, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been reported.

Тиотропия бромида моногидрад HANDIHALER is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, or any components of this product. In clinical trials and postmarketing experience with Тиотропия бромида моногидрад 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

Тиотропия бромида моногидрад is intended as a once-daily maintenance treatment for COPD and asthma and should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. In the event of an acute attack, a rapid-acting beta2-agonist should be used.

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 Тиотропия бромида моногидрад. If such a reaction occurs, therapy with Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад.

Paradoxical Bronchospasm

Inhaled medicines, including Тиотропия бромида моногидрад, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with Тиотропия бромида моногидрад should be stopped and other treatments considered.

Worsening Of Narrow-Angle Glaucoma

Тиотропия бромида моногидрад 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

Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад should be monitored closely for anticholinergic side effects.

Patient Counseling Information

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

Not For Acute Use

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

Immediate Hypersensitivity Reactions

Inform patients that anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, may occur after administration of Тиотропия бромида моногидрад. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.

Paradoxical Bronchospasm

Inform patients that Тиотропия бромида моногидрад can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Тиотропия бромида моногидрад.

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 aerosol cloud 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 Тиотропия бромида моногидрад, 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.

Treatment Of Asthma

Instruct asthma patients that the maximum benefits may only be apparent after 4 to 8 weeks of Тиотропия бромида моногидрад treatment.

Instructions For Administering Тиотропия бромида моногидрад

It is important for patients to understand how to correctly administer SPIRIVA inhalation spray using the Тиотропия бромида моногидрад inhaler. Instruct patients that SPIRIVA inhalation spray should only be administered via the Тиотропия бромида моногидрад inhaler and the Тиотропия бромида моногидрад inhaler should not be used for administering other medications.

Instruct patients that priming Тиотропия бромида моногидрад is essential to ensure appropriate content of the medication in each actuation.

When using the unit for the first time, the SPIRIVA RESPIMAT cartridge is inserted into the Тиотропия бромида моногидрад inhaler and the unit is primed. Тиотропия бромида моногидрад patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then to 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.

Instruct caregivers of children that Тиотропия бромида моногидрад should be used with an adult's assistance.

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 maximum 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

Risk Summary

The limited human data with Тиотропия бромида моногидрад use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. There are risks to the mother and the fetus associated with poorly controlled asthma in pregnancy. 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.

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.

Clinical Considerations

Disease-Associated Maternal and/or Embryo-Fetal Risk

Poorly or moderately controlled asthma in pregnancy increases the maternal risk of preeclampsia and infant prematurity, low birth weight, and small for gestational age. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.

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 maximum recommended human daily inhalation dose (MRHDID), respectively (on a mcg/m² basis at inhalation doses of 1471 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/m² 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/m² basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at 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).

Lactation

Risk Summary

There are no data on the presence of tiotropium in human milk, the effects on the breastfed infant, or the effects on milk production. Tiotropium is present in milk of lactating rats; however, due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Тиотропия бромида моногидрад and any potential adverse effects on the breastfed child from Тиотропия бромида моногидрад or from the underlying maternal condition.

Data

The distribution of tiotropium bromide into milk was investigated after a single intravenous administration of 10 mg/kg to lactating rats. Tiotropium and/or its metabolites are present in the milk of lactating rats at concentrations above those in plasma.

Pediatric Use

The safety and efficacy of Тиотропия бромида моногидрад 2.5 mcg have been established in pediatric patients aged 6 to 17 years with asthma in 6 clinical trials up to 1 year in duration. In three clinical trials, 327 patients aged 12 to 17 years with asthma were treated with Тиотропия бромида моногидрад 2.5 mcg; in three additional clinical trials, 345 patients aged 6 to 11 years with asthma were treated with Тиотропия бромида моногидрад 2.5 mcg. Patients in these age groups demonstrated efficacy results similar to those observed in patients aged 18 years and older with asthma.

The safety and efficacy of Тиотропия бромида моногидрад have not been established in pediatric patients less than 6 years of age. The safety of Тиотропия бромида моногидрад 2.5 mcg has been studied in pediatric patients with asthma aged 1 to 5 years who were on background treatment of at least ICS in one placebo-controlled clinical trial of 12 weeks duration (36 treated with SPIRIVA RESPIMAT 2.5 mcg and 34 with placebo RESPIMAT). In this study, Тиотропия бромида моногидрад or placebo RESPIMAT was delivered with the AeroChamber Plus Flow-Vu^® valved holding chamber with facemask once daily. The majority of the patients in the trial were male (60.4%) and Caucasian (76.2%) with a mean age of 3.1 years. The adverse reaction profile was similar to that observed in adults and older pediatric patients.

In Vitro Characterization Studies With Valved Holding Chamber

Dose delivery and fine particle fraction of SPIRIVA RESPIMAT when administered via a valved holding chamber (AeroChamber Plus Flow-Vu® with or without face mask) was assessed by in vitro studies.

Inspiratory flow rates of 4.9, 8.0, and 12.0 L/min in combination with holding times of 0, 2, 5, and 10 seconds were tested. The flow rates were selected to be representative of inspiratory flow rates of children aged 6 to 12 months, 2 to 5 years, and over 5 years, respectively.

Table 3 summarizes the results for delivered dose under the respective test conditions and configurations.

Table 3 : In Vitro Medication Delivery through AeroChamber Plus Flow-Vu® Valved Holding Chamber with Face Mask at Different low Rates and Holding Times Using the Dose 2.5 mcg (as two actuations)

The in vitro study data show a reduction of the absolute delivered dose through the valved holding chamber. However, in terms of dose per kilogram of body weight the data suggest that under all tested conditions the dose of Тиотропия бромида моногидрад delivered by the AeroChamber Plus Flow-Vu® valved holding chamber with mask will at least lead to a dosing comparable to that of adults without use of a holding chamber and mask (Table 3). The fine particle fraction ( < 5 μm) across the flow rates used in these studies was 69-89% of the delivered dose through the valved holding chamber, consistent with the removal of the coarser fraction by the holding chamber. In contrast, the fine particle fraction for Тиотропия бромида моногидрад delivered without a holding chamber typically represents approximately 60% of the delivered dose.

Geriatric Use

Based on available data, no adjustment of Тиотропия бромида моногидрад dosage in geriatric patients is warranted.

Thirty nine percent of SPIRIVA RESPIMAT clinical trial patients with COPD were between 65 and 75 years of age and 14% were greater than or equal to 75 years of age. Approximately seven percent of Тиотропия бромида моногидрад clinical trial patients with asthma were greater than or equal to 65 years of age. The adverse drug reaction profiles were similar in the older population compared to the patient population overall.

Renal Impairment

Patients with moderate to severe renal impairment (creatinine clearance of < 60 mL/min) treated with Тиотропия бромида моногидрад should be monitored closely for anticholinergic side effects.

Hepatic Impairment

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Not For Acute Use

Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER. If such a reaction occurs, therapy with Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER. In addition, Тиотропия бромида моногидрад HANDIHALER should be used with caution in patients with severe hypersensitivity to milk proteins.

Paradoxical Bronchospasm

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

Worsening Of Narrow-Angle Glaucoma

Тиотропия бромида моногидрад 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

Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

Instruct patients on how to correctly administer Тиотропия бромида моногидрад capsules using the HANDIHALER device. Instruct patients that Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад capsules are for oral inhalation only and must not be swallowed.

Instruct patients always to store Тиотропия бромида моногидрад capsules in sealed blisters and to remove only one Тиотропия бромида моногидрад capsule immediately before use or its effectiveness may be reduced. Instruct patients to discard unused additional Тиотропия бромида моногидрад 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. Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER is administered to a nursing woman.

Pediatric Use

Тиотропия бромида моногидрад HANDIHALER is not indicated for use in children. The safety and effectiveness of Тиотропия бромида моногидрад HANDIHALER in pediatric patients have not been established.

Geriatric Use

Based on available data, no adjustment of Тиотропия бромида моногидрад HANDIHALER dosage in geriatric patients is warranted.

Of the total number of patients who received Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER and the comparator groups for most events. Dry mouth increased with age in the Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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

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.

Since the same active ingredient (tiotropium bromide) is administered to COPD and asthma patients, prescribers and patients should take into account that the observed adverse reactions could be relevant for both patient populations independent of dosage strength.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

The Тиотропия бромида моногидрад clinical development program included ten placebo controlled clinical trials in COPD. Two trials were four-week cross-over trials and eight were parallel group trials. The parallel group trials included a three week dose-ranging trial, two 12-week trials, three 48-week trials, and two trials of 4-week and 24-week duration conducted for a different program that contained tiotropium bromide 5 mcg treatment arms. The primary safety database consists of pooled data from the 7 randomized, parallel-group, double-blind, placebo-controlled studies of 4-48 weeks in treatment duration. These trials included 6565 adult COPD patients (75% males and 25% females) 40 years of age and older. Of these patients, 3282 patients were treated with Тиотропия бромида моногидрад 5 mcg and 3283 received placebo. The SPIRIVA RESPIMAT 5 mcg group was composed mostly of Caucasians (78%) with a mean age of 65 years and a mean baseline percent predicted post-bronchodilator FEV₁ of 46%.

In these 7 clinical trials, 68.3% of patients exposed to Тиотропия бромида моногидрад 5 mcg reported an adverse event compared to 68.7% of patients in the placebo group. There were 68 deaths in the Тиотропия бромида моногидрад 5 mcg treatment group (2.1%) and 52 deaths (1.6%) in patients who received placebo. The percentage of Тиотропия бромида моногидрад patients who discontinued due to an adverse event were 7.3% compared to 10% with placebo patients. The percentage of Тиотропия бромида моногидрад 5 mcg patients who experienced a serious adverse event were 15.0% compared to 15.1% with placebo patients. In both groups, the adverse event most commonly leading to discontinuation was COPD exacerbation (SPIRIVA RESPIMAT 2.0%, placebo 4.0%) which was also the most frequent serious adverse event. The most commonly reported adverse reactions were pharyngitis, cough, dry mouth, and sinusitis (Table 1). Other adverse reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, dysuria, and urinary retention.

Table 1 shows all adverse reactions that occurred with an incidence of > 3% in the Тиотропия бромида моногидрад 5 mcg treatment group, and a higher incidence rate on Тиотропия бромида моногидрад 5 mcg than on placebo.

Table 1 : Number (Percentage) of COPD Patients Exposed to Тиотропия бромида моногидрад 5 mcg with Adverse Reactions > 3% (and Higher than Placebo): Pooled Data from 7 Clinical Trials with Treatment Periods Ranging between 4 and 48 Weeks in COPD Patients

Other reactions that occurred in the Тиотропия бромида моногидрад 5 mcg group at an incidence of 1% to 3% and at a higher incidence rate on Тиотропия бромида моногидрад 5 mcg than on placebo included: Cardiac disorders: palpitations; Gastrointestinal disorders: constipation, gastroesophageal reflux disease, oropharyngeal candidiasis; Nervous system disorders: dizziness; Respiratory, thoracic, and mediastinal disorders: dysphonia; Skin and subcutaneous tissue disorders: pruritus, rash; Renal and urinary disorders: urinary tract infection.

Less Common Adverse Reactions

Among the adverse reactions observed in the clinical trials with an incidence of < 1% and at a higher incidence rate on Тиотропия бромида моногидрад 5 mcg than on placebo were: dysphagia, gingivitis, intestinal obstruction including ileus paralytic, joint swelling, dysuria, urinary retention, epistaxis, laryngitis, angioedema, dry skin, skin infection, and skin ulcer.

Clinical Trials Experience In Asthma

Adult Patients

Тиотропия бромида моногидрад 2.5 mcg has been compared to placebo in four placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in adult patients (aged 18 to 75 years) with asthma. The safety data described below are based on one 1-year, two 6-month and one 12-week randomized, double-blind, placebo-controlled trials in a total of 2849 asthma patients on background treatment of at least ICS or ICS and long-acting beta agonist (ICS/LABA). Of these patients, 787 were treated with Тиотропия бромида моногидрад at the recommended dose of 2.5 mcg once-daily; 59.7% were female and 47.5% were Caucasian with a mean age of 43.7 years and a mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV₁) of 90.0% at baseline.

Table 2 shows all adverse reactions that occurred with an incidence of > 2% in the Тиотропия бромида моногидрад 2.5 mcg treatment group, and a higher incidence rate on Тиотропия бромида моногидрад 2.5 mcg than on placebo.

Table 2 : Number (Percentage) of Asthma Patients Exposed to Тиотропия бромида моногидрад 2.5 mcg with Adverse Reactions > 2% (and Higher than Placebo): Pooled Data from 4 Adult Clinical Trials with Treatment Periods Ranging between 12 and 52 Weeks in Asthma Patients

Other reactions that occurred in the Тиотропия бромида моногидрад 2.5 mcg group at an incidence of 1% to 2% and at a higher incidence rate on Тиотропия бромида моногидрад 2.5 mcg than on placebo included: Nervous system disorders: dizziness; Gastrointestinal disorders: oropharyngeal candidiasis, diarrhea; Respiratory, thoracic, and mediastinal disorders: cough, rhinitis allergic; Renal and urinary disorders: urinary tract infection; General disorders and administration site conditions: pyrexia; and Vascular disorders: hypertension.

Less Common Adverse Reactions

Among the adverse reactions observed in the clinical trials with an incidence of 0.5% to < 1% and at a higher incidence rate on Тиотропия бромида моногидрад 2.5 mcg than on placebo were: palpitations, dysphonia, acute tonsillitis, tonsillitis, rhinitis, herpes zoster, gastroesophageal reflux disease, oropharyngeal discomfort, abdominal pain upper, insomnia, hypersensitivity (including immediate reactions), angioedema, dehydration, arthralgia, muscle spasms, pain in extremity, chest pain, hepatic function abnormal, liver function test abnormal.

Adolescent Patients Aged 12 To 17 years

Тиотропия бромида моногидрад 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in adolescent patients with asthma. The safety data described below are based on one 48-week and one 12-week double-blind, placebo-controlled trials in a total of 789 adolescent asthma patients on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 252 were treated with Тиотропия бромида моногидрад at the recommended dose of 2.5 mcg once-daily; 63.9% were male and 95.6% were Caucasian with a mean age of 14.3 years and a mean post-bronchodilator percent predicted FEV₁ of 98.3% at baseline. The adverse reaction profile for adolescent patients with asthma was comparable to that observed in adult patients with asthma.

Pediatric Patients Aged 6 To 11 years

Тиотропия бромида моногидрад 2.5 mcg has been compared to placebo in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in pediatric patients aged 6 to 11 years with asthma. The safety data are based on one 48-week and one 12-week double-blind, placebo-controlled trials in a total of 801 pediatric asthma patients aged 6 to 11 years on background treatment of at least ICS or ICS plus one or more controller. Of these patients, 271 were treated with SPIRIVA RESPIMAT at the recommended dose of 2.5 mcg once-daily; 71.2% were male and 86.7% were Caucasian with a mean age of 8.9 years and a mean postbronchodilator percent predicted FEV₁ of 97.9% at baseline. The adverse reaction profile for pediatric patients aged 6 to 11 years with asthma was comparable to that observed in adult patients with asthma.

Тиотропия бромида моногидрад 5 mcg also has been compared to placebo in seven placebo-controlled parallel-group trials ranging from 12 to 52 weeks of treatment duration in 4149 adult patients (aged 18 to 75 years) with asthma and in two placebo-controlled parallel-group trials ranging from 12 to 48 weeks of treatment duration in 789 adolescent patients (1370 adults and 264 adolescents receiving Тиотропия бромида моногидрад 5 mcg once-daily). The adverse reaction profile for Тиотропия бромида моногидрад 5 mcg in patients with asthma was comparable to that observed with Тиотропия бромида моногидрад 2.5 mcg in patients with asthma.

Postmarketing Experience

In addition to the adverse reactions observed during the Тиотропия бромида моногидрад clinical trials in COPD, the following adverse reactions have been observed during post-approval use of SPIRIVA RESPIMAT 5 mcg and another tiotropium formulation, SPIRIVA® HandiHaler® (tiotropium bromide inhalation powder). 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.

• Glaucoma, intraocular pressure increased, vision blurred,
• Atrial fibrillation, tachycardia, supraventricular tachycardia,
• Bronchospasm,
• Glossitis, stomatitis,
• Dehydration,
• Insomnia,
• Hypersensitivity (including immediate reactions), and urticaria.

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 Тиотропия бромида моногидрад HANDIHALER in 2663 patients. Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥ 3% in the Тиотропия бромида моногидрад HANDIHALER group in the 1-year placebo-controlled trials where the rates in the Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER treatment group, but were < 1% in excess of the placebo group.

Other reactions that occurred in the Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад HANDIHALER group where the rates in the Тиотропия бромида моногидрад HANDIHALER group exceeded placebo by ≥ 1%, adverse reactions included (Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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 Тиотропия бромида моногидрад 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.

Hohe Dosen von Tiotropium können zu anticholinergen Anzeichen und Symptomen führen. Nach einer inhalativen Einzeldosis von bis zu 282 µg Tiotropium-Trockenpulver bei 6 gesunden Probanden gab es jedoch keine systemischen anticholinergen Nebenwirkungen. Trockener Mund / Hals und trockene Nasenschleimhaut traten dosisabhängig [10-40 µg täglich] auf, nachdem bei gesunden Probanden eine 14-tägige Dosierung von bis zu 40 µg Tiotropiumbromid-Inhalationslösung vorgenommen worden war.

Die Behandlung von Überdosierungen besteht aus dem Absetzen von Тиотропия бромида моногидрад zusammen mit der Einrichtung einer geeigneten symptomatischen und / oder unterstützenden Therapie.

Hohe Dosen von Tiotropium können zu anticholinergen Anzeichen und Symptomen führen. Nach einer inhalativen Einzeldosis von bis zu 282 µg Tiotropium bei 6 gesunden Probanden gab es jedoch keine systemischen anticholinergen Nebenwirkungen. In einer Studie mit 12 gesunden Probanden wurden nach wiederholtem täglichem Einatmen von 141 µg Tiotropium bilaterale Bindehautentzündung und Mundtrockenheit beobachtet.

Die Behandlung von Überdosierungen besteht aus dem Absetzen von Тиотропия бромида моногидрад HANDIHALER zusammen mit der Einrichtung einer geeigneten symptomatischen und / oder unterstützenden Therapie.

Versehentliche Einnahme

Eine akute Vergiftung durch versehentliche orale Einnahme von Тиотропия бромида моногидрад-Kapseln ist unwahrscheinlich, da sie systemisch nicht gut aufgenommen werden.

Ein Fall von Überdosierung wurde aus Erfahrung nach dem Inverkehrbringen gemeldet. Es wurde berichtet, dass eine Patientin über einen Zeitraum von 2,5 Tagen 30 Kapseln eingeatmet hat und einen veränderten psychischen Status, Zittern, Bauchschmerzen und schwere Verstopfung entwickelt hat. Der Patient wurde ins Krankenhaus eingeliefert, Тиотропия бромида моногидрад HANDIHALER wurde abgesetzt und die Verstopfung mit einem Einlauf behandelt. Der Patient erholte sich und wurde am selben Tag entlassen.

Herzelektrophysiologie

In einer multizentrischen, randomisierten, doppelblinden Studie mit Tiotropium-Trockenpulver zum Einatmen, an der 198 Patienten mit COPD teilnahmen, war die Anzahl der Probanden mit Änderungen gegenüber dem zu Studienbeginn korrigierten QT-Intervall von 30 bis 60 ms in der SPIRIVA-Gruppe im Vergleich zu Placebo höher . Dieser Unterschied wurde sowohl bei den Bazett (QTcB) [20 (20%) Patienten als auch bei den Bazett (QTcB) offensichtlich. 12 (12%) Patienten] und Fredericia (QTcF) [16 (16%) Patienten vs. 1 (1%) Patient] Korrekturen der QT für die Herzfrequenz. Keine Patienten in einer der Gruppen hatten entweder QTcB oder QTcF von> 500 ms. Andere klinische Studien mit SPIRIVA zeigten keine Wirkung des Arzneimittels auf QTc-Intervalle.

Die Wirkung von Tiotropium-Trockenpulver zum Einatmen im QT-Intervall wurde auch in einer randomisierten, placebokontrollierten und positiv kontrollierten Crossover-Studie an 53 gesunden Probanden bewertet. Die Probanden erhielten 12 Tage lang Tiotropium-Inhalationspulver 18 µg, 54 µg (3-fache der empfohlenen Dosis) oder Placebo. EKG-Bewertungen wurden zu Studienbeginn und während des gesamten Dosierungsintervalls nach der ersten und letzten Dosis der Studienmedikamente durchgeführt. Im Vergleich zu Placebo betrug die maximale mittlere Veränderung des studienspezifischen QTc-Intervalls gegenüber dem Ausgangswert 3,2 ms und 0,8 ms für 18 µg bzw. 54 µg Tiotropium-Inhalationspulver. Kein Proband zeigte einen neuen Beginn von QTc> 500 ms oder QTc-Änderungen gegenüber dem Ausgangswert von ≥ 60 ms.

Herzelektrophysiologie

In einer multizentrischen, randomisierten, doppelblinden Studie mit Tiotropium-Trockenpulver zum Einatmen, an der 198 Patienten mit COPD teilnahmen, war die Anzahl der Probanden mit Änderungen gegenüber dem zu Studienbeginn korrigierten QT-Intervall von 30 bis 60 ms in der Gruppe Тиотропия бромида моногидидад im Vergleich zu HANDIHALER. Dieser Unterschied wurde sowohl bei den Bazett (QTcB) [20 (20%) Patienten als auch bei den Bazett (QTcB) offensichtlich. 12 (12%) Patienten] und Fredericia (QTcF) [16 (16%) Patienten vs. 1 (1%) Patient] Korrekturen der QT für die Herzfrequenz. Keine Patienten in einer der Gruppen hatten entweder QTcB oder QTcF von> 500 ms. Andere klinische Studien mit Тиотропия бромида моногидрад HANDIHALER haben keine Wirkung des Arzneimittels auf QTc-Intervalle festgestellt.

Die Wirkung von Tiotropium-Trockenpulver zum Einatmen im QT-Intervall wurde auch in einer randomisierten, placebokontrollierten und positiv kontrollierten Crossover-Studie an 53 gesunden Probanden bewertet. Die Probanden erhielten 12 Tage lang Tiotropium-Trockenpulver zum Einatmen von 18 µg, 54 µg (3-fache der empfohlenen Dosis) oder Placebo. EKG-Bewertungen wurden zu Studienbeginn und während des gesamten Dosierungsintervalls nach der ersten und letzten Dosis der Studienmedikamente durchgeführt. Im Vergleich zu Placebo betrug die maximale mittlere Veränderung des studienspezifischen QTc-Intervalls gegenüber dem Ausgangswert 3,2 ms und 0,8 ms für Tiotropium-Trockenpulver zum Einatmen von 18 µg bzw. 54 µg. Kein Proband zeigte einen neuen Beginn von QTc> 500 ms oder QTc-Änderungen gegenüber dem Ausgangswert von ≥ 60 ms.

Tiotropium wird als Inhalationsspray verabreicht. Einige der nachstehend beschriebenen pharmakokinetischen Daten wurden mit höheren Dosen als für die Therapie empfohlen erhalten. Eine spezielle pharmakokinetische Studie bei Patienten mit COPD, in der einmal täglich Tiotropium bewertet wurde, das aus dem RESPIMAT-Inhalator (5 µg) und als Inhalationspulver (18 µg) aus dem HandiHaler geliefert wurde, führte zu einer ähnlichen systemischen Exposition zwischen den beiden Produkten.

Absorption

Nach dem Einatmen der Lösung durch junge gesunde Probanden legen Daten zur Urinausscheidung nahe, dass ungefähr 33% der inhalierten Dosis den systemischen Kreislauf erreichen. Orale Lösungen von Tiotropium haben eine absolute Bioverfügbarkeit von 2% bis 3%. Es wird nicht erwartet, dass Lebensmittel aus demselben Grund die Aufnahme von Tiotropium beeinflussen. Nach 4-wöchiger Тиотропия бромида моногидрад wurden nach der täglichen Dosierung maximale Tiotropium-Plasmakonzentrationen 5-7 Minuten nach Inhalation bei COPD- und Asthmapatienten beobachtet.

Verteilung

Das Medikament hat eine Plasmaproteinbindung von 72% und zeigt nach intravenöser Dosis ein Verteilungsvolumen von 32 l / kg an junge gesunde Probanden. Lokale Konzentrationen in der Lunge sind nicht bekannt, aber die Art der Verabreichung legt wesentlich höhere Konzentrationen in der Lunge nahe. Studien an Ratten haben gezeigt, dass Tiotropium die Blut-Hirn-Schranke nicht durchdringt.

Beseitigung

Stoffwechsel

Das Ausmaß des Stoffwechsels ist gering. Dies geht aus einer Urinausscheidung von 74% der unveränderten Substanz nach einer intravenösen Dosis an junge gesunde Probanden hervor. Tiotropium, ein Ester, wird nonenzymatisch an den Alkohol N-Methylscopin und Dithienylglykolsäure gespalten, von denen keiner an Muskarinrezeptoren bindet.

In vitro Experimente mit menschlichen Lebermikrosomen und menschlichen Hepatozyten legen nahe, dass ein Bruchteil der verabreichten Dosis (74% einer intravenösen Dosis werden unverändert im Urin ausgeschieden, so dass 25% für den Metabolismus übrig bleiben) durch Cytochrom P450-abhängige Oxidation und anschließende Glutathionkonjugation zu einer Vielzahl von metabolisiert wird Phase-II-Metaboliten. Dieser enzymatische Weg kann durch CYP450 2D6- und 3A4-Inhibitoren wie Chinidin, Ketoconazol und Gestoden gehemmt werden. Somit sind CYP450 2D6 und 3A4 an dem Stoffwechsel beteiligt, der für die Eliminierung eines kleinen Teils der verabreichten Dosis verantwortlich ist. In vitro Studien mit menschlichen Lebermikrosomen zeigten, dass Tiotropium in supra-therapeutischen Konzentrationen CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 oder 3A4 nicht hemmt.

Ausscheidung

Die terminale Halbwertszeit von Tiotropium bei COPD- und Asthmapatienten nach einmal täglicher Inhalation beträgt 25 bzw. 44 Stunden. Die Gesamtclearance betrug nach einer intravenösen Dosis bei jungen gesunden Probanden 880 ml / min. Intravenös verabreichtes Tiotropiumbromid wird hauptsächlich unverändert im Urin ausgeschieden (74%). Nach 21 Tagen einmal täglicher Inhalation von 5 µg der Lösung durch Patienten mit COPD beträgt die 24-Stunden-Harnausscheidung 18,6% (0,93 µg) der Dosis. Die renale Clearance von Tiotropium überschreitet die Kreatinin-Clearance, was auf eine Sekretion in den Urin hinweist. Im Vergleich dazu wurden 12,8% (0,32 µg) der Dosis über 24 Stunden im Steady-State nach Inhalation von 2,5 µg bei Asthmapatienten unverändert im Urin ausgeschieden. Nach chronischer einmal täglicher Inhalation durch COPD- und Asthmapatienten wurde der pharmakokinetische Steady-State am Tag 7 ohne anschließende Akkumulation erreicht.

Tiotropium wird durch Einatmen von trockenem Pulver verabreicht. Einige der nachstehend beschriebenen pharmakokinetischen Daten wurden mit höheren Dosen als für die Therapie empfohlen erhalten. Eine spezielle pharmakokinetische Studie bei Patienten mit COPD, in der einmal täglich Tiotropium bewertet wurde, das vom RESPIMAT-Inhalator (5 µg) und als Inhalationspulver (18 µg) vom HANDIHALER-Gerät geliefert wurde, führte zu einer ähnlichen systemischen Exposition zwischen den beiden Produkten.

Absorption

Nach dem Einatmen von trockenem Pulver durch junge gesunde Freiwillige deutet die absolute Bioverfügbarkeit von 19,5% darauf hin, dass die Fraktion, die die Lunge erreicht, hoch bioverfügbar ist. Orale Lösungen von Tiotropium haben eine absolute Bioverfügbarkeit von 2-3%. Es wird nicht erwartet, dass Lebensmittel die Aufnahme von Tiotropium beeinflussen. Maximale Tiotropium-Plasmakonzentrationen wurden 7 Minuten nach dem Einatmen beobachtet.

Verteilung

Tiotropium ist zu 72% an Plasmaprotein gebunden und hatte nach intravenöser Verabreichung an junge gesunde Probanden ein Verteilungsvolumen von 32 l / kg. Lokale Konzentrationen in der Lunge sind nicht bekannt, aber die Art der Verabreichung legt wesentlich höhere Konzentrationen in der Lunge nahe. Studien an Ratten haben gezeigt, dass Tiotropium die Blut-Hirn-Schranke nicht ohne weiteres durchdringt.

Beseitigung

Die terminale Halbwertszeit von Tiotropium bei COPD-Patienten nach einmal täglicher Inhalation von 5 µg Tiotropium betrug ungefähr 25 Stunden. Die Gesamtclearance betrug nach intravenöser Verabreichung bei jungen gesunden Probanden 880 ml / min. Nach chronischer einmal täglicher Trockenpulverinhalation durch COPD-Patienten wurde der pharmakokinetische Steady State am Tag 7 erreicht, ohne dass sich danach eine Akkumulation aufzeichnete.

Stoffwechsel

Das Ausmaß des Stoffwechsels ist gering. Dies geht aus einer Urinausscheidung von 74% der unveränderten Substanz nach einer intravenösen Dosis an junge gesunde Probanden hervor. Tiotropium, ein Ester, wird nonenzymatisch an den Alkohol N-Methylscopin und Dithienylglykolsäure gespalten, von denen keiner an Muskarinrezeptoren bindet.

In vitro Experimente mit menschlichen Lebermikrosomen und menschlichen Hepatozyten legen nahe, dass ein Bruchteil der verabreichten Dosis (74% einer intravenösen Dosis werden unverändert im Urin ausgeschieden, so dass 25% für den Metabolismus übrig bleiben) durch Cytochrom P450-abhängige Oxidation und anschließende Glutathionkonjugation zu einer Vielzahl von metabolisiert wird Phase-II-Metaboliten. Dieser enzymatische Weg kann durch CYP450 2D6- und 3A4-Inhibitoren wie Chinidin, Ketoconazol und Gestoden gehemmt werden. Somit sind CYP450 2D6 und 3A4 an dem Stoffwechsel beteiligt, der für die Eliminierung eines kleinen Teils der verabreichten Dosis verantwortlich ist. In vitro Studien mit menschlichen Lebermikrosomen zeigten, dass Tiotropium in supra-therapeutischen Konzentrationen CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 oder 3A4 nicht hemmte.

Ausscheidung

Intravenös verabreichtes Tiotropiumbromid wird hauptsächlich unverändert im Urin ausgeschieden (74%). Nach dem Einatmen von trockenem Pulver bei COPD-Patienten im Steady-State betrug die Urinausscheidung über 24 Stunden 7% (1,3 μg) der unveränderten Dosis. Die renale Clearance von Tiotropium überschreitet die Kreatinin-Clearance, was auf eine Sekretion in den Urin hinweist.