Tudorza Pressair: Package Insert and Label Information

TUDORZA PRESSAIR- aclidinium bromide powder, metered
AstraZeneca Pharmaceuticals LP

1 INDICATIONS AND USAGE

TUDORZA® PRESSAIR® (aclidinium bromide inhalation powder) is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

2 DOSAGE AND ADMINISTRATION

The recommended dose of TUDORZA PRESSAIR is one oral inhalation of 400 mcg, twice daily (morning and evening approximately 12 hours apart).

3 DOSAGE FORMS AND STRENGTHS

Inhalation Powder. TUDORZA PRESSAIR is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.

4 CONTRAINDICATIONS

The use of TUDORZA PRESSAIR is contraindicated in the following conditions:

Severe hypersensitivity to milk proteins [see Warnings and Precautions (5.5)]
Hypersensitivity to aclidinium bromide or any of the excipients [see Warnings and Precautions (5.5)]

5 WARNINGS AND PRECAUTIONS

5.1 Not for Acute Use

TUDORZA PRESSAIR is intended as a twice-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).

5.2 Paradoxical Bronchospasm

Inhaled medicines, including TUDORZA PRESSAIR, may cause paradoxical bronchospasm. If this occurs, treatment with TUDORZA PRESSAIR should be stopped and other treatments considered.

5.3 Worsening of Narrow-Angle Glaucoma

TUDORZA PRESSAIR 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.

5.4 Worsening of Urinary Retention

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

5.5 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions, including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, have occurred after administration of TUDORZA PRESSAIR. If such a reaction occurs, therapy with TUDORZA PRESSAIR should be stopped at once and alternative treatments should be considered.

6 ADVERSE REACTIONS

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

Paradoxical bronchospasm [see Warnings and Precautions (5.2)]
Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.3)]
Worsening of urinary retention [see Warnings and Precautions (5.4)]
Immediate hypersensitivity reactions [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

3-Month and 6-Month Trials

TUDORZA PRESSAIR was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily.

The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1 ) percent predicted of 48%. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.

Table 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the TUDORZA PRESSAIR group in the two 3-month and one 6-month placebo-controlled trials where the rates in the TUDORZA PRESSAIR group exceeded placebo.

Table 1: Adverse Reactions (% Patients) in Placebo-Controlled Clinical Trials

Treatment

Adverse Reactions

TUDORZA PRESSAIR

Placebo

Preferred Term

(N=636)

(N=640)

n (%)

n (%)

Headache

42 (6.6)

32 (5.0)

Nasopharyngitis

35 (5.5)

25 (3.9)

Cough

19 (3.0)

14 (2.2)

Diarrhea

17 (2.7)

9 (1.4)

Sinusitis

11 (1.7)

5 (0.8)

Rhinitis

10 (1.6)

8 (1.2)

Toothache

7 (1.1)

5 (0.8)

Fall

7 (1.1)

3 (0.5)

Vomiting

7 (1.1)

3 (0.5)

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were diabetes mellitus, dry mouth, 1st degree AV block, osteoarthritis, cardiac failure, and cardio-respiratory arrest.

Long-term Safety Trials

TUDORZA PRESSAIR was studied in three long-term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe COPD. Two of these trials were extensions of the 3-month trials, and one was a dedicated long-term safety trial. In these trials, 891 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long-term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long-term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo-controlled trials.

Long-Term Trial of up to 3-Years

In a long-term safety trial with 3630 moderate to very severe COPD patients with previous major cardiac events or cardiovascular risk factors at baseline, the adverse reactions reported with a frequency ≥2% in the TUDORZA PRESSAIR group in which the exposure-adjusted incidence rate exceeds the placebo group were nausea, back pain, cough, hypertension, sinusitis, constipation, arthralgia, anemia, muscle spasms, cardiac failure congestive, cellulitis, and gastroesophageal reflux disease. No other new adverse reactions were identified.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of drug TUDORZA PRESSAIR. 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.

In postmarketing experience with TUDORZA PRESSAIR, immediate hypersensitivity reactions, including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching have been reported. Additionally, nausea, dysphonia, blurred vision, urinary retention, tachycardia, and stomatitis have been observed.

7 DRUG INTERACTIONS

In vitro studies suggest limited potential for CYP450-related metabolic drug interactions, thus no formal drug interaction studies have been performed with TUDORZA PRESSAIR [see Clinical Pharmacology (12.3)].

7.1 Sympathomimetics, Methylxanthines, Steroids

In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of COPD including sympathomimetics (short-acting beta2 agonists), methylxanthines, and oral and inhaled steroids showed no increases in adverse drug reactions.

7.2 Anticholinergics

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of TUDORZA PRESSAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well controlled studies of TUDORZA PRESSAIR in pregnant women to inform drug associated risks.

No adverse developmental effects were seen with inhalation administration of aclidinium bromide to pregnant rats and rabbits during organogenesis at 15 or 20 times, respectively, the maximum recommended human daily inhaled dose (MRHDID). However, reduced pup weights were seen when pregnant rats continued inhalation administration through lactation at 5 times the MRHDID of aclidinium bromide. Adverse developmental effects occurred when rabbits were orally dosed with aclidinium bromide at approximately 1,400 times the MRHDID [see Data ].

The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. 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.

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-17, no evidence of structural alterations was observed at approximately 15 times the MRHDID [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, in a pre- and post-natal development study, decreased pup weights were observed when pregnant rats were exposed from gestation day 6 and continuing during the lactation period at approximately 5 times the MRHDID [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

In an embryo-fetal development study in pregnant Himalayan rabbits administered inhaled doses of aclidinium bromide during the period of organogenesis from gestation days 6-19, no evidence of structural alterations was observed at approximately 20 times the MRHDID [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, in another embryo-fetal development study in pregnant Himalayan rabbits dosed orally from gestation days 6-19, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the MRHDID [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the MRHDID [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.

8.2 Lactation

Risk Summary

There are no available data on the effects of TUDORZA PRESSAIR or aclidinium bromide on the breastfed child or on milk production or presence in human milk. Aclidinium bromide is present in milk of lactating female rats [see Data ]. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TUDORZA PRESSAIR and any potential adverse effects on the breastfed child from TUDORZA PRESSAIR or from the underlying maternal condition.

Data

In a pharmacokinetic study, levels of radioactivity in milk and plasma in rats were measured after a single intravenous dose of 1 mg/kg of radiolabeled aclidinium bromide on approximately post-natal day 14 [see Use in Specific Populations (8.1)]. The maximum concentration of radioactivity [14 C-aclidinium] in milk was measured at 6 hours post-dose and was found to be 10-14 times higher than in plasma.

8.4 Pediatric Use

TUDORZA PRESSAIR is approved for use in the maintenance treatment of bronchospasm associated with COPD. COPD does not normally occur in children. The safety and effectiveness of TUDORZA PRESSAIR in pediatric patients have not been established.

8.5 Geriatric Use

Of the 636 COPD patients exposed to TUDORZA PRESSAIR 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for TUDORZA PRESSAIR, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

The pharmacokinetics of TUDORZA PRESSAIR were investigated in subjects with normal renal function and in subjects with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3)]. No clinically significant differences in aclidinium pharmacokinetics were noted between these populations. Based on available data for TUDORZA PRESSAIR, no adjustment of dosage in renally impaired subjects is warranted.

8.7 Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of TUDORZA PRESSAIR were not studied [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

10.1 Human Experience

No case of overdose has been reported in clinical studies with TUDORZA PRESSAIR. There were no systemic anticholinergic or other adverse effects following a single inhaled dose of up to 6,000 mcg aclidinium bromide (7.5 times the RHDD) in 16 healthy volunteers.

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