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Tudorza Pressair Side Effects Center
Medical Editor: Charles Patrick Davis, MD, PhD
Tudorza Pressair (aclidinium bromide) inhalation powder is an anticholinergic indicated for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. The most common side effects of Tudorza Pressair are headache, common cold symptoms, and cough.
Tudorza Pressair is available for oral inhalation only. The recommended dosage of Tudorza Pressair is one inhalation (400 mcg of aclidinium bromide) twice daily. Some serious side effects of Tudorza Pressair can include sudden shortness of breath immediately after taking this medicine and new or worsened pressure in the eyes (acute narrow-angle glaucoma).There are no adequate and well controlled studies in pregnant women. Tudorza Pressair should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Excretion of aclidinium bromide, the active ingredient in Tudorza Pressair into human breast milk is probable. There are no human studies that have investigated the effects of Tudorza Pressair on breastfed infants. Caution should be exercised when Tudorza Pressair is administered to nursing women. The safety and effectiveness in the pediatric population has not been established.
Our Tudorza Pressair Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Tudorza Pressair FDA Prescribing Information: Side Effects
Mechanism Of Action
Aclidinium bromide is a long-acting antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of aclidinium bromide is predominantly a site-specific effect.
In a thorough QT Study, 200 mcg and 800 mcg TUDORZA PRESSAIR was administered to healthy volunteers once daily for 3 days; no effects on prolongation of QT interval were observed using QTcF heart-rate correction methods.
Additionally, the effect of TUDORZA PRESSAIR on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr Holter monitoring. No clinically significant effects on cardiac rhythm were observed.
The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers. Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.
Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.
Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases. Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.
Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%. Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium. Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces. The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis. After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.
Formal drug interaction studies were not performed. In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose. Therefore, it is unlikely that aclidinium bromide causes CYP450 related drug interactions [see DRUG INTERACTIONS].
The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients [Use in Specific Populations (8.5)].
The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients [see Use in Specific Populations].
The effects of hepatic impairment on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors [see Use in Specific Populations].
Chronic Obstructive Pulmonary Disease (COPD)
The TUDORZA PRESSAIR clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).
Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had a forced expiratory volume in one second (FEV1) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 0.7. Trial A included TUDORZA PRESSAIR doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough FEV1 and serial FEV1 in patients treated with the TUDORZA PRESSAIR 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the TUDORZA PRESSAIR 400 mcg twice daily dose (Figure 1).
Figure 1: Change from baseline in FEV1 Over Time
(prior to and after administration of study drug) at Week 1 in Trial A
Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with COPD. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.
These clinical trials evaluated TUDORZA PRESSAIR 400 mcg twice daily (636 patients) and placebo (640 patients). TUDORZA PRESSAIR 400 mcg resulted in statistically significantly greater bronchodilation as measured by change from baseline in morning pre-dose FEV1 at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials (Table 2).
Table 2: Change from Baseline in Trough FEV1 (L) at
|Treatment Arm||Baseline||Change from Baseline LS Mean (SE)||Treatment Difference LS Mean (95% CI)|
|Trial B (N = 375)|
|Aclidinium 400 mcg||1.33||0.10 (0.01)||0.12 (0.08, 0.16)|
|Trial C (N=359)|
|Aclidinium 400 mcg||1.25||0.06 (0.02)||0.07 (0.03, 0.12)|
|Trial D* (N = 542)|
|Aclidinium 400 mcg||1.51||0.06 (0.02)||0.11 (0.07, 0.14)|
|SE=standard error, and LS mean=least square mean. LS
mean, and 95% confidence interval were obtained from an ANCOVA model with
change from baseline in trough FEV1 as response, with treatment group and sex
as factors and baseline trough FEV1 and age as covariates.
*In the 6-month Trial D, placebo adjusted change from baseline in Trough FEV1 at 24 weeks was 0.13 (0.09, 0.17).
Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3month trials (Trial B) are displayed in Figure 2. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3-or 6month treatment period.
Figure 2: Mean FEV1 Over Time (prior to and after
administration of study drug) on Day 1 and Week 12 in Subset of Patients
Participating in the 12 hours Serial Spirometry Substudy for Trial B (a 3-month
Mean peak improvements in FEV1, for TUDORZA PRESSAIR relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with TUDORZA PRESSAIR used less daily rescue albuterol during the trial compared to patients treated with placebo.
Read the entire FDA prescribing information for Tudorza Pressair (Aclidinium Bromide)
Additional Tudorza Pressair Information
- Tudorza Pressair Drug Interactions Center: aclidinium bromide inhl
- Tudorza Pressair Side Effects Center
- Tudorza Pressair FDA Approved Prescribing Information including Dosage
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