Componenti:
Opzione di trattamento:
Revisione medica di Fedorchenko Olga Valeryevna, Pharmacy Ultimo aggiornamento in data 20.03.2022
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Primi 20 medicinali con gli stessi componenti:
Trattamento di mantenimento della malattia polmonare ostruttiva cronica
Тиотропиум-натив (bromuro di tiotropio) è indicato per il trattamento di mantenimento a lungo termine, una volta al giorno, del broncospasmo associato alla broncopneumopatia cronica ostruttiva (BPCO), inclusi bronchite cronica ed enfisema. Тиотропиум-натив è indicato per ridurre le esacerbazioni nei pazienti con BPCO.
Importante limitazione d'uso
Тиотропиум-натив NON è indicato per il sollievo del broncospasmo acuto.
Trattamento di mantenimento dell'asma
Тиотропиум-натив è un broncodilatatore indicato per il trattamento di mantenimento dell'asma a lungo termine, una volta al giorno, in pazienti di età pari o superiore a 6 anni.
Importante limitazione d'uso
Тиотропиум-натив NON è indicato per il sollievo del broncospasmo acuto.
Тиотропиум-натив HANDIHALER (polvere per inalazione di bromuro di iotropio) è indicato per il trattamento di mantenimento a lungo termine, una volta al giorno, del broncospasmo associato alla broncopneumopatia cronica ostruttiva (BPCO), inclusa bronchite cronica ed enfisema. Тиотропиум-натив HANDIHALER è indicato per ridurre le esacerbazioni nei pazienti con BPCO.
Per ricevere l'intera dose di farmaci, Тиотропиум-натив deve essere somministrato come due inalazioni una volta al giorno. Non assumere più di una dose (2 inalazioni) in 24 ore.
Prima del primo utilizzo, la cartuccia SPIRIVA RESPIMAT viene inserita nell'inalatore Тиотропиум-натив e l'unità viene adescata. Quando si utilizza l'unità per la prima volta, i pazienti devono azionare l'inalatore verso il suolo fino a quando non è visibile una nuvola di aerosol e quindi ripetere il processo altre tre volte. L'unità viene quindi considerata innescata e pronta per l'uso. Se non utilizzati per più di 3 giorni, i pazienti devono azionare l'inalatore una volta per preparare l'inalatore per l'uso. Se non utilizzati per più di 21 giorni, i pazienti devono azionare l'inalatore fino a quando non è visibile una nuvola di aerosol e quindi ripetere il processo altre tre volte per preparare l'inalatore per l'uso.
Malattia polmonare ostruttiva cronica
Il dosaggio raccomandato per i pazienti con BPCO è di 2 inalazioni di Тиотропиум-натив 2,5 mcg per attuazione una volta al giorno; la dose totale è pari a 5 mcg di Тиотропиум-натив.
Asma
Il dosaggio raccomandato per i pazienti con asma è di 2 inalazioni di Тиотропиум-натив 1,25 mcg per attuazione una volta al giorno; la dose totale è pari a 2,5 mcg di Тиотропиум-натив. Nel trattamento dell'asma, i massimi benefici nella funzione polmonare possono richiedere fino a 4-8 settimane di dosaggio.
Popolazioni speciali
Non è necessario alcun aggiustamento del dosaggio per pazienti geriatrici, con problemi epatici o con insufficienza renale. Tuttavia, i pazienti con insufficienza renale da moderata a grave trattati con SPIRIVA RESPIMAT devono essere attentamente monitorati per gli effetti anticolinergici.
Solo per inalazione orale. Non ingerire le capsule Тиотропиум-натив, poiché gli effetti previsti sui polmoni non saranno ottenuti. Il contenuto delle capsule Тиотропиум-натив deve essere utilizzato solo con il dispositivo HANDIHALER
La dose raccomandata di Тиотропиум-натив HANDIHALER è di due inalazioni del contenuto di polvere di una capsula Тиотропиум-натив, una volta al giorno, con il dispositivo HANDIHALER. Non assumere più di una dose in 24 ore.
Per la somministrazione di Тиотропиум-натив HANDIHALER, una capsula Тиотропиум-натив viene posizionata nella camera centrale del dispositivo HANDIHALER. La capsula Тиотропиум-натив viene perforata premendo e rilasciando il pulsante di perforazione verde sul lato del dispositivo HANDIHALER. La formulazione di tiotropio viene dispersa nel flusso d'aria quando il paziente inala attraverso il boccaglio
Non è necessario alcun aggiustamento del dosaggio per pazienti geriatrici, con problemi epatici o con insufficienza renale. Tuttavia, i pazienti con insufficienza renale da moderata a grave trattati con Тиотропиум-натив HANDIHALER devono essere attentamente monitorati per gli effetti anticolinergici.
Тиотропиум-натив è controindicato nei pazienti con ipersensibilità al tiotropio, all'ipratropio o a qualsiasi componente di questo prodotto. Negli studi clinici con Тиотропиум-натив, sono state riportate reazioni di ipersensibilità immediata, incluso angioedema (incluso gonfiore delle labbra, della lingua o della gola), prurito o eruzione cutanea.
Тиотропиум-натив HANDIHALER è controindicato nei pazienti con ipersensibilità al tiotropio, all'ipratropio o ad eventuali componenti di questo prodotto. Negli studi clinici e nell'esperienza post-marketing con Тиотропиум-натив HANDIHALER, sono state riportate reazioni di ipersensibilità immediata, incluso angioedema (incluso gonfiore delle labbra, della lingua o della gola), prurito o eruzione cutanea.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Not For Acute Use
Тиотропиум-натив 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 Тиотропиум-натив. If such a reaction occurs, therapy with Тиотропиум-натив 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 Тиотропиум-натив.
Paradoxical Bronchospasm
Inhaled medicines, including Тиотропиум-натив, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as albuterol. Treatment with Тиотропиум-натив should be stopped and other treatments considered.
Worsening Of Narrow-Angle Glaucoma
Тиотропиум-натив 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
Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив. Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.
Paradoxical Bronchospasm
Inform patients that Тиотропиум-натив can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Тиотропиум-натив.
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 Тиотропиум-натив, 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 Тиотропиум-натив treatment.
Instructions For Administering Тиотропиум-натив
It is important for patients to understand how to correctly administer SPIRIVA inhalation spray using the Тиотропиум-натив inhaler. Instruct patients that SPIRIVA inhalation spray should only be administered via the Тиотропиум-натив inhaler and the Тиотропиум-натив inhaler should not be used for administering other medications.
Instruct patients that priming Тиотропиум-натив 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 Тиотропиум-натив inhaler and the unit is primed. Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив and any potential adverse effects on the breastfed child from Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 2.5 mcg; in three additional clinical trials, 345 patients aged 6 to 11 years with asthma were treated with Тиотропиум-натив 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 Тиотропиум-натив have not been established in pediatric patients less than 6 years of age. The safety of Тиотропиум-натив 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, Тиотропиум-натив 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)
Flow Rate (L/min) and corresponding age | Mask | Holding Time (seconds) | Mean Medication Delivery through Aero Chamber Plus Flow-Vu® per Dose (mcg) | Body Weight 50th Percentile (kg)a | Medication Delivered per Dose (ng/kg)b |
4.9 (6 to 12 Months) | small | 0 | 0.85 | 7 5-9 9 | 86-113 |
2 | 0.86 | 87-115 | |||
5 | 0.55 | 56-73 | |||
10 | 0.62 | 63-83 | |||
8.0 (2 to 5 Years) | medium | 0 | 0.74 | 12.3-18.0 | 41-60 |
2 | 0 93 | 52-76 | |||
5 | 0.72 | 40-59 | |||
10 | 0.57 | 32-46 | |||
12.0 ( > 5 Years) | medium | 0 | 1.16 | 18 0 | 64 |
2 | 0.96 | 53 | |||
5 | 0.78 | 43 | |||
10 | 0.61 | 34 | |||
a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2009). Body weight values correspond to the average of the 50 percentile weight for boys and girls at the ages indicated. b Inhalation of Тиотропиум-натив 2.5 mcg dose (as two actuations) in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 2.5 mcg, or 36 ng/kg. |
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 Тиотропиум-натив 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 Тиотропиум-натив delivered without a holding chamber typically represents approximately 60% of the delivered dose.
Geriatric Use
Based on available data, no adjustment of Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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
Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER. If such a reaction occurs, therapy with Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER. In addition, Тиотропиум-натив HANDIHALER should be used with caution in patients with severe hypersensitivity to milk proteins.
Paradoxical Bronchospasm
Inhaled medicines, including Тиотропиум-натив HANDIHALER, may cause paradoxical bronchospasm. If this occurs, it should be treated immediately with an inhaled shortacting beta2-agonist such as albuterol. Treatment with Тиотропиум-натив HANDIHALER should be stopped and other treatments considered.
Worsening Of Narrow-Angle Glaucoma
Тиотропиум-натив 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
Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER
Instruct patients on how to correctly administer Тиотропиум-натив capsules using the HANDIHALER device. Instruct patients that Тиотропиум-натив 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 Тиотропиум-натив capsules are for oral inhalation only and must not be swallowed.
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. Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER is administered to a nursing woman.
Pediatric Use
Тиотропиум-натив HANDIHALER is not indicated for use in children. The safety and effectiveness of Тиотропиум-натив HANDIHALER in pediatric patients have not been established.
Geriatric Use
Based on available data, no adjustment of Тиотропиум-натив HANDIHALER dosage in geriatric patients is warranted.
Of the total number of patients who received Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER and the comparator groups for most events. Dry mouth increased with age in the Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 5 mcg reported an adverse event compared to 68.7% of patients in the placebo group. There were 68 deaths in the Тиотропиум-натив 5 mcg treatment group (2.1%) and 52 deaths (1.6%) in patients who received placebo. The percentage of Тиотропиум-натив patients who discontinued due to an adverse event were 7.3% compared to 10% with placebo patients. The percentage of Тиотропиум-натив 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 Тиотропиум-натив 5 mcg treatment group, and a higher incidence rate on Тиотропиум-натив 5 mcg than on placebo.
Table 1 : Number (Percentage) of COPD Patients Exposed to Тиотропиум-натив 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
Body System (Reaction)* | Тиотропиум-натив 5 mcg [n=3282] | Placebo [n=3283] |
Gastrointestinal Disorders | ||
Dry mouth | 134 (4.1) | 52 (1.6) |
Infections and Infestations | ||
Pharyngitis | 378 (11.5) | 333 (10.1) |
Respiratory, Thoracic, and MediastinalDisorders | ||
Cough | 190 (5.8) | 182 (5.5) |
Sinusitis | 103 (3.1) | 88 (2.7) |
*Adverse reactions include a grouping of similar terms |
Other reactions that occurred in the Тиотропиум-натив 5 mcg group at an incidence of 1% to 3% and at a higher incidence rate on Тиотропиум-натив 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 Тиотропиум-натив 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
Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 2.5 mcg treatment group, and a higher incidence rate on Тиотропиум-натив 2.5 mcg than on placebo.
Table 2 : Number (Percentage) of Asthma Patients Exposed to Тиотропиум-натив 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
Body System (Reaction)* | Тиотропиум-натив 2.5 mcg [n=787] | Placebo [n=735] |
Respiratory, Thoracic, and Mediastinal Disorders | ||
Pharyngitis | 125 (15.9) | 91 (12.4) |
Sinusitis | 21 (2.7) | 10 (1.4) |
Bronchitis | 26 (3.3) | 10 (1.4) |
Nervous System Disorders | ||
Headache | 30 (3.8) | 20 (2.7) |
*Adverse reactions include a grouping of similar terms |
Other reactions that occurred in the Тиотропиум-натив 2.5 mcg group at an incidence of 1% to 2% and at a higher incidence rate on Тиотропиум-натив 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 Тиотропиум-натив 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
Тиотропиум-натив 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 Тиотропиум-натив 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
Тиотропиум-натив 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.
Тиотропиум-натив 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 Тиотропиум-натив 5 mcg once-daily). The adverse reaction profile for Тиотропиум-натив 5 mcg in patients with asthma was comparable to that observed with Тиотропиум-натив 2.5 mcg in patients with asthma.
Postmarketing Experience
In addition to the adverse reactions observed during the Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER in 2663 patients. Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥ 3% in the Тиотропиум-натив HANDIHALER group in the 1-year placebo-controlled trials where the rates in the Тиотропиум-натив HANDIHALER group exceeded placebo by ≥ 1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison.
Table 1 : Adverse Reactions (% Patients) in One-Year COPD Clinical Trials
Body System (Event) | Placebo-Controlled Trials | Ipratropium-Controlled Trials | ||
Тиотропиум-натив (n = 550) | Placebo (n = 371) | Тиотропиум-натив (n = 356) | Ipratropium (n = 179) | |
Body as a Whole | ||||
Chest Pain (non-specific) | 7 | 5 | 5 | 2 |
Edema, Dependent | 5 | 4 | 3 | 5 |
Gastrointestinal System Disorders | ||||
Dry Mouth | 16 | 3 | 12 | 6 |
Dyspepsia | 6 | 5 | 1 | 1 |
Abdominal Pain | 5 | 3 | 6 | 6 |
Constipation | 4 | 2 | 1 | 1 |
V omiting | 4 | 2 | 1 | 2 |
Musculoskeletal System | ||||
Myalgia | 4 | 3 | 4 | 3 |
Resistance Mechanism Disorders | ||||
Infection | 4 | 3 | 1 | 3 |
Moniliasis | 4 | 2 | 3 | 2 |
Respiratory System (Upper) | ||||
Upper Respiratory Tract Infection | 41 | 37 | 43 | 35 |
Sinusitis | 11 | 9 | 3 | 2 |
Pharyngitis | 9 | 7 | 7 | 3 |
Rhinitis | 6 | 5 | 3 | 2 |
Epistaxis | 4 | 2 | 1 | 1 |
Skin and Appendage Disorders | ||||
Rash | 4 | 2 | 2 | 2 |
Urinary System | ||||
Urinary Tract Infection | 7 | 5 | 4 | 2 |
Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥ 3% in the Тиотропиум-натив HANDIHALER treatment group, but were < 1% in excess of the placebo group.
Other reactions that occurred in the Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with Тиотропиум-натив 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 Тиотропиум-натив HANDIHALER group where the rates in the Тиотропиум-натив HANDIHALER group exceeded placebo by ≥ 1%, adverse reactions included (Тиотропиум-натив 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 Тиотропиум-натив 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 Тиотропиум-натив 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.
Alte dosi di tiotropio possono portare a segni e sintomi anticolinergici. Tuttavia, non ci sono stati effetti avversi anticolinergici sistemici a seguito di una singola dose inalata fino a 282 mcg di polvere secca di tiotropio in 6 volontari sani. La bocca secca / gola e la mucosa nasale secca si sono verificate in modo dose-dipendente [10-40 mcg al giorno], dopo una somministrazione di 14 giorni di una soluzione per inalazione di bromuro di tiotropio fino a 40 mcg in soggetti sani.
Il trattamento del sovradosaggio consiste nell'interruzione di Тиотропиум-натив insieme all'istituzione di un'adeguata terapia sintomatica e / o di supporto.
Alte dosi di tiotropio possono portare a segni e sintomi anticolinergici. Tuttavia, non ci sono stati effetti avversi anticolinergici sistemici a seguito di una singola dose inalata fino a 282 mcg di tiotropio in 6 volontari sani. In uno studio su 12 volontari sani, sono state osservate congiuntivite bilaterale e secchezza delle fauci a seguito di ripetute inalazioni giornaliere di 141 mcg di tiotropio.
Il trattamento del sovradosaggio consiste nell'interruzione di Тиотропиум-натив HANDIHALER insieme all'istituzione di un'adeguata terapia sintomatica e / o di supporto.
Ingestione accidentale
L'intossicazione acuta da ingestione orale involontaria di capsule Тиотропиум-натив è improbabile poiché non è ben assorbita dal punto di vista sistemico.
Un caso di sovradosaggio è stato riportato dall'esperienza post-marketing. È stato riferito che una paziente ha inalato 30 capsule per un periodo di 2,5 giorni e ha sviluppato uno stato mentale alterato, tremori, dolore addominale e costipazione grave. Il paziente è stato ricoverato in ospedale, Тиотропиум-натив HANDIHALER è stato sospeso e la costipazione è stata trattata con un clistere. Il paziente si riprese e fu dimesso lo stesso giorno.
Elettrofisiologia cardiaca
In uno studio multicentrico, randomizzato, in doppio cieco con polvere secca di tiotropio per inalazione che ha arruolato 198 pazienti con BPCO, il numero di soggetti con variazioni dall'intervallo QT corretto al basale da 30 a 60 msec era più elevato nel gruppo SPIRIVA rispetto al placebo . Questa differenza era evidente usando entrambi i pazienti Bazett (QTcB) [20 (20%) vs. 12 (12%) pazienti] e Fredericia (QTcF) [16 (16%) pazienti vs. 1 (1%) paziente] correzioni di QT per la frequenza cardiaca. Nessun paziente in entrambi i gruppi aveva QTcB o QTcF> 500 msec. Altri studi clinici con SPIRIVA non hanno rilevato un effetto del farmaco sugli intervalli QTc.
L'effetto della polvere secca di tiotropio per inalazione sull'intervallo QT è stato anche valutato in uno studio crossover randomizzato, controllato con placebo e positivo su 53 volontari sani. I soggetti hanno ricevuto polvere per inalazione di tiotropio 18 mcg, 54 mcg (3 volte la dose raccomandata) o placebo per 12 giorni. Le valutazioni ECG sono state eseguite al basale e per tutto l'intervallo di dosaggio dopo la prima e l'ultima dose di farmaci in studio. Rispetto al placebo, la variazione media massima rispetto al basale nell'intervallo QTc specifico dello studio era di 3,2 msec e 0,8 msec per polvere per inalazione di tiotropio 18 mcg e 54 mcg, rispettivamente. Nessun soggetto ha mostrato una nuova insorgenza di QTc> 500 msec o QTc da basale di ≥ 60 msec.
Elettrofisiologia cardiaca
In uno studio multicentrico, randomizzato, in doppio cieco con polvere secca di tiotropio per inalazione che ha arruolato 198 pazienti con BPCO, il numero di soggetti con variazioni dall'intervallo QT corretto per il basale da 30 a 60 msec era più alto nel gruppo Тиотропиум-натив HANDIHALER rispetto al placebo. Questa differenza era evidente usando entrambi i pazienti Bazett (QTcB) [20 (20%) vs. 12 (12%) pazienti] e Fredericia (QTcF) [16 (16%) pazienti vs. 1 (1%) paziente] correzioni di QT per la frequenza cardiaca. Nessun paziente in entrambi i gruppi aveva QTcB o QTcF> 500 msec. Altri studi clinici con Тиотропиум-натив HANDIHALER non hanno rilevato un effetto del farmaco sugli intervalli QTc.
L'effetto della polvere secca di tiotropio per inalazione sull'intervallo QT è stato anche valutato in uno studio crossover randomizzato, controllato con placebo e positivo su 53 volontari sani. I soggetti hanno ricevuto polvere secca di tiotropio per inalazione 18 mcg, 54 mcg (3 volte la dose raccomandata) o placebo per 12 giorni. Le valutazioni ECG sono state eseguite al basale e per tutto l'intervallo di dosaggio dopo la prima e l'ultima dose di farmaci in studio. Rispetto al placebo, la variazione media massima rispetto al basale nell'intervallo QTc specifico dello studio era di 3,2 msec e 0,8 msec per polvere secca di tiotropio per inalazione rispettivamente di 18 mcg e 54 mcg. Nessun soggetto ha mostrato una nuova insorgenza di QTc> 500 msec o QTc da basale di ≥ 60 msec.
Il tiotropio viene somministrato come spray per inalazione. Alcuni dei dati di farmacocinetica descritti di seguito sono stati ottenuti con dosi più elevate di quelle raccomandate per la terapia. Uno studio di farmacocinetica dedicato su pazienti con BPCO che valutano il tiotropio una volta al giorno erogato dall'inalatore RESPIMAT (5 mcg) e come polvere per inalazione (18 mcg) dall'HandiHaler ha determinato un'esposizione sistemica simile tra i due prodotti.
Assorbimento
Dopo l'inalazione della soluzione da parte di giovani volontari sani, i dati sull'escrezione urinaria suggeriscono che circa il 33% della dose inalata raggiunge la circolazione sistemica. Le soluzioni orali di tiotropio hanno una biodisponibilità assoluta dal 2% al 3%. Non si prevede che il cibo influenzi l'assorbimento del tiotropio per lo stesso motivo. Dopo 4 settimane di somministrazione Тиотропиум-натив una volta al giorno, sono state osservate concentrazioni plasmatiche massime di tiotropio 5-7 minuti dopo l'inalazione nei pazienti con BPCO e asma.
Distribuzione
Il farmaco ha un legame con le proteine plasmatiche del 72% e mostra un volume di distribuzione di 32 L / kg dopo una dose endovenosa a giovani volontari sani. Le concentrazioni locali nel polmone non sono note, ma la modalità di somministrazione suggerisce concentrazioni sostanzialmente più elevate nel polmone. Studi sui ratti hanno dimostrato che il tiotropio non penetra nella barriera emato-encefalica.
Eliminazione
Metabolismo
L'estensione del metabolismo è piccola. Ciò è evidente da un'escrezione urinaria del 74% della sostanza immodificata dopo una dose endovenosa a giovani volontari sani. Il tiotropio, un estere, viene scosso non enzimaticamente dall'alcool N-metilscopina e acido ditienilglicolico, nessuno dei quali si lega ai recettori muscarinici.
In vitro esperimenti con microsomi epatici umani ed epatociti umani suggeriscono che una frazione della dose somministrata (il 74% di una dose endovenosa viene escreta immodificata nelle urine, lasciando il 25% per il metabolismo) viene metabolizzata dall'ossidazione dipendente dal citocromo P450 e dalla successiva coniugazione del glutatione a una varietà di metaboliti di fase II. Questa via enzimatica può essere inibita dagli inibitori del CYP450 2D6 e 3A4, come chinidina, ketoconazolo e gestodene. Pertanto, CYP450 2D6 e 3A4 sono coinvolti nella via metabolica responsabile dell'eliminazione di una piccola parte della dose somministrata. In vitro studi condotti con microsomi epatici umani hanno dimostrato che il tiotropio nelle concentrazioni sopraterapeutiche non inibisce CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 o 3A4.
Escrezione
L'emivita terminale del tiotropio nei pazienti con BPCO e asma dopo inalazione giornaliera è rispettivamente di 25 e 44 ore. La clearance totale è stata di 880 ml / min dopo una dose endovenosa in giovani volontari sani. Il bromuro di tiotropio somministrato per via endovenosa viene escreto principalmente immodificato nelle urine (74%). Dopo 21 giorni di inalazione giornaliera di 5 mcg di soluzione da parte di pazienti con BPCO, l'escrezione urinaria 24 ore è del 18,6% (0,93 mcg) della dose. La clearance renale del tiotropio supera la clearance della creatinina, indicando la secrezione nelle urine. In confronto, il 12,8% (0,32 mcg) della dose è stato escreto immodificato nelle urine per 24 ore allo stato stazionario dopo inalazione di 2,5 mcg nei pazienti con asma. Dopo inalazione cronica una volta al giorno da parte di pazienti con BPCO e asma, lo stato stazionario farmacocinetico è stato raggiunto entro il giorno 7 senza accumulo in seguito.
Il tiotropio viene somministrato per inalazione di polvere secca. Alcuni dei dati di farmacocinetica descritti di seguito sono stati ottenuti con dosi più elevate di quelle raccomandate per la terapia. Uno studio di farmacocinetica dedicato su pazienti con BPCO che valutano il tiotropio una volta al giorno erogato dall'inalatore RESPIMAT (5 mcg) e come polvere per inalazione (18 mcg) dal dispositivo HANDIHALER ha determinato un'esposizione sistemica simile tra i due prodotti.
Assorbimento
Dopo l'inalazione di polvere secca da parte di giovani volontari sani, la biodisponibilità assoluta del 19,5% suggerisce che la frazione che raggiunge il polmone è altamente biodisponibile. Le soluzioni orali di tiotropio hanno una biodisponibilità assoluta del 2-3%. Non si prevede che il cibo influenzi l'assorbimento del tiotropio. Le concentrazioni plasmatiche massime di tiotropio sono state osservate 7 minuti dopo l'inalazione.
Distribuzione
Il tiotropio è legato al 72% alle proteine plasmatiche e ha avuto un volume di distribuzione di 32 L / kg dopo somministrazione endovenosa a giovani volontari sani. Le concentrazioni locali nel polmone non sono note, ma la modalità di somministrazione suggerisce concentrazioni sostanzialmente più elevate nel polmone. Studi sui ratti hanno dimostrato che il tiotropio non penetra facilmente nella barriera emato-encefalica.
Eliminazione
L'emivita terminale del tiotropio nei pazienti con BPCO dopo inalazione una volta al giorno di 5 mcg di tiotropio è stata di circa 25 ore. La clearance totale è stata di 880 ml / min dopo somministrazione endovenosa in giovani volontari sani. Dopo inalazione cronica di polvere secca una volta al giorno da parte dei pazienti con BPCO, lo stato stazionario farmacocinetico è stato raggiunto entro il giorno 7 senza accumulo in seguito.
Metabolismo
L'estensione del metabolismo è piccola. Ciò è evidente da un'escrezione urinaria del 74% della sostanza immodificata dopo una dose endovenosa a giovani volontari sani. Il tiotropio, un estere, viene scosso non enzimaticamente dall'alcool N-metilscopina e acido ditienilglicolico, nessuno dei quali si lega ai recettori muscarinici.
In vitro esperimenti con microsomi epatici umani ed epatociti umani suggeriscono che una frazione della dose somministrata (il 74% di una dose endovenosa viene escreta immodificata nelle urine, lasciando il 25% per il metabolismo) viene metabolizzata dall'ossidazione dipendente dal citocromo P450 e dalla successiva coniugazione del glutatione a una varietà di metaboliti di fase II. Questa via enzimatica può essere inibita dagli inibitori del CYP450 2D6 e 3A4, come chinidina, ketoconazolo e gestodene. Pertanto, CYP450 2D6 e 3A4 sono coinvolti nella via metabolica responsabile dell'eliminazione di una piccola parte della dose somministrata. In vitro studi condotti con microsomi epatici umani hanno dimostrato che il tiotropio nelle concentrazioni sopraterapeutiche non ha inibito CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 o 3A4.
Escrezione
Il bromuro di tiotropio somministrato per via endovenosa viene escreto principalmente immodificato nelle urine (74%). Dopo inalazione di polvere secca nei pazienti con BPCO allo stato stazionario, l'escrezione urinaria è stata del 7% (1,3 μg) della dose invariata nell'arco di 24 ore. La clearance renale del tiotropio supera la clearance della creatinina, indicando la secrezione nelle urine.
However, we will provide data for each active ingredient