Infortispir Respimat

Maintenance Treatment Of COPD

Infortispir Respimat is a long-acting beta₂-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations Of Use

Infortispir Respimat is not indicated to treat acute deteriorations of COPD.

Infortispir Respimat is not indicated to treat asthma. The safety and effectiveness of Infortispir Respimat in asthma have not been established.

The recommended dose of Infortispir Respimat is two inhalations once-daily at the same time of the day. Do not use STRIVERDI RESPIMAT more than two inhalations every 24 hours.

Prior to first use, the Infortispir Respimat cartridge is inserted into the Infortispir Respimat inhaler and the unit is primed. When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally-impaired patients. There are no data available for use of Infortispir Respimat in severe hepatically impaired patients.

All LABA are contraindicated in patients with asthma without use of a long-term asthma control medication. Infortispir Respimat is not indicated for the treatment of asthma.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Asthma-Related Death

• Data from a large placebo-controlled study in asthma patients showed that long-acting beta₂-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta₂-adrenergic agonists.
• A 28-week, placebo-controlled US study comparing the safety of another long-acting beta₂-adrenergic agonist (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of long-acting beta₂-adrenergic agonists, including Infortispir Respimat. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with Infortispir Respimat has been conducted. The safety and efficacy of Infortispir Respimat in patients with asthma have not been established. Infortispir Respimat is not indicated for the treatment of asthma.

Deterioration Of Disease And Acute Episodes

Infortispir Respimat should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Infortispir Respimat has not been studied in patients with acutely deteriorating COPD. The use of Infortispir Respimat in this setting is inappropriate.

Infortispir Respimat should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Infortispir Respimat has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta₂-agonist.

When beginning Infortispir Respimat, patients who have been taking inhaled, short-acting beta₂-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing Infortispir Respimat, the healthcare provider should also prescribe an inhaled, short-acting beta₂-agonist and instruct the patient on how it should be used. Increasing inhaled beta₂-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Infortispir Respimat no longer controls symptoms of bronchoconstriction, or the patient's inhaled, short-acting beta₂-agonist becomes less effective or the patient needs more inhalation of short-acting beta₂-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of Infortispir Respimat beyond the recommended dose is not appropriate in this situation.

Excessive Use Of Infortispir Respimat And Use With Long-Acting Beta₂-Agonists

As with other inhaled drugs containing beta₂-adrenergic agents, Infortispir Respimat should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Paradoxical Bronchospasm

As with other inhaled beta₂-agonists, Infortispir Respimat may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Infortispir Respimat should be discontinued immediately and alternative therapy instituted.

Cardiovascular Effects

Infortispir Respimat, like other beta₂-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and/or symptoms. If such effects occur, Infortispir Respimat may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Long acting beta₂-adrenergic agonists should be administered with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, and hypertension.

Co-existing Conditions

Infortispir Respimat, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, in patients with known or suspected prolongation of the QT interval, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

Hypokalemia And Hyperglycemia

Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta₂-adrenergic agonists may produce increases in plasma glucose.

In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment , which may increase the susceptibility for cardiac arrhythmias.

Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of Infortispir Respimat with the rates similar to those for placebo controls. Infortispir Respimat has not been investigated in patients whose diabetes mellitus is not well controlled.

Hypersensitivity Reactions

Immediate hypersensitivity reactions, including angioedema, may occur after administration of Infortispir Respimat. If such a reaction occurs, therapy with Infortispir Respimat should be stopped at once and alternative treatment should be considered.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide and Instructions for Use).

Asthma-Related Death

Inform patients that LABA, such as Infortispir Respimat, increase the risk of asthma-related death. STRIVERDI RESPIMAT is not indicated for the treatment of asthma.

Preparation For Use And Priming

Instruct patients that priming Infortispir Respimat is essential to ensure appropriate content of the medication in each actuation.

When using the unit for the first time, the Infortispir Respimat cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit is primed. Infortispir Respimat patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use. If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.

Not For Acute Symptoms

Infortispir Respimat is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta₂-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)

Instruct patients to notify their physician immediately if they experience any of the following:

• Worsening of symptoms
• Decreasing effectiveness of inhaled, short-acting beta₂-agonists
• Need for more inhalations than usual of inhaled, short-acting beta₂-agonists
• Significant decrease in lung function as outlined by the physician

Instruct patients not to stop therapy with Infortispir Respimat without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta₂-Agonists

Patients who have been taking inhaled, short-acting beta₂-agonists on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

When patients are prescribed Infortispir Respimat, other inhaled medications containing long-acting beta₂-agonists should not be used. Patients should not use more than the recommended once-daily dose of Infortispir Respimat. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.

Risks Associated With Beta₂-Agonist Therapy

Inform patients of adverse effects associated with beta₂-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year inhalation studies were conducted in rats and mice to assess the carcinogenic potential of olodaterol. Lifetime treatment of female rats induced leiomyomas of the mesovarium at doses of 25.8 and 270 mcg/kg/day (approximately 18- and 198-fold, respectively, the MRHDID on an AUC basis). No tumor findings were observed in male rats at doses up to 270 mcg/kg/day (approximately 230-fold the MRHDID on an AUC basis). Lifetime treatment of female mice induced leiomyomas and leiomyosarcomas of the uterus at doses ≥ 76.9 mcg/kg/day (approximately 106-fold the MRHDID on an AUC basis). No tumor findings were observed in male mice at doses up to 255 mcg/kg/day (approximately 455-fold the MRHDID on an AUC basis). Increases in leiomyomas and leiomyosarcomas of the female rodent reproductive tract have been similarly demonstrated with other β2-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Olodaterol was not mutagenic in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of micronuclei in rats after intravenous doses. The increased frequency of micronuclei was likely related to drug enhanced (compensatory) erythropoiesis. The mechanism for induction of micronuclei formation is likely not relevant at clinical exposures.

Olodaterol did not impair male or female fertility in rats at inhalation doses up to 3,068 mcg/kg/day (approximately 2,322 times the MRHDID on an AUC basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C.

There are no adequate and well-controlled studies with Infortispir Respimat in pregnant women. Infortispir Respimat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Infortispir Respimat was not teratogenic in rats at inhalation doses approximately 2,731 times the maximum recommended human daily inhalation dose (MRHDID) on an AUC basis (at a rat maternal inhalation dose of 1,054 mcg/kg/day). Placental transfer of Infortispir Respimat was observed in pregnant rats.

Infortispir Respimat has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7,130 times the MRHDID in adults on an AUC basis (at a rabbit maternal inhalation dose of 2,489 mcg/kg/day). Infortispir Respimat exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at an inhalation dose approximately 1,353 times the MRHDID in adults on an AUC basis (at a rabbit maternal inhalation dose of 974 mcg/kg/day).

Labor And Delivery

There are no adequate and well-controlled human studies that have investigated the effects of Infortispir Respimat on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of Infortispir Respimat during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Olodaterol, the active component of Infortispir Respimat, and/or its metabolites are excreted into the milk of lactating rats. Excretion of olodaterol and/or its metabolites into human milk is probable. There are no human studies that have investigated the effects of Infortispir Respimat on nursing infants. Caution should be exercised when Infortispir Respimat is administered to nursing women.

Pediatric Use

Infortispir Respimat is not indicated for use in children. The safety and effectiveness of Infortispir Respimat in the pediatric population have not been established.

Geriatric Use

Based on available data, no adjustment of STRIVERDI RESPIMAT dosage in geriatric patients is necessary.

Of the 876 patients who received Infortispir Respimat at the recommended dose of 5 mcg once-daily in the clinical studies from the pooled 1-year database, 485 were less than or equal to 65 years of age and 391 (44.6%) were greater than 65 years of age.

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

Hepatic Impairment

Subjects with mild and moderate hepatic impairment showed no changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. A study in subjects with severe hepatic impairment was not performed.

Renal Impairment

Subjects with severe renal impairment showed no clinically relevant changes in Cmax or AUC compared to their healthy controls.

Long-acting beta₂-adrenergic agonists, such as STRIVERDI RESPIMAT, increase the risk of asthma-related death. Infortispir Respimat is not indicated for the treatment of asthma.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

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

The Infortispir Respimat clinical development program included seven dose-ranging trials and eight confirmatory trials. Four of the confirmatory trials were 6week cross-over trials and four were 48-week parallel group trials. Adverse reactions observed in the dose-ranging trials and four 6-week cross-over trials were consistent with those observed in the 48-week parallel group trials, which formed the primary safety database.

The primary safety database consisted of pooled data from the four 48-week double-blind, active and placebo-controlled, parallel group confirmatory clinical trials. These trials included 3104 adult COPD patients (77% males and 23% females) 40 years of age and older. Of these patients, 876 and 883 patients were treated with Infortispir Respimat 5 mcg and 10 mcg once-daily, respectively. The Infortispir Respimat groups were composed of mostly Caucasians (66%) with a mean age of 64 years and a mean percent predicted FEV₁ at baseline of 44% for both the 5 mcg and 10 mcg treatment groups. Control arms for comparison included placebo in all four trials plus formoterol 12 mcg in two trials.

In these four clinical trials, seventy-two percent (72%) of patients exposed to any dose of Infortispir Respimat reported an adverse reaction compared to 71% in the placebo group. The proportion of patients who discontinued due to an adverse reaction was 7.2% for Infortispir Respimat treated patients compared to 8.8% for placebo treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD. The most common serious adverse reactions were COPD exacerbation, pneumonia, and atrial fibrillation.

Table 1 shows all adverse drug reactions reported by at least 2% of patients (and higher than placebo) who received Infortispir Respimat 5 mcg during the 48week trials.

Table 1 : Number and frequency of adverse drug reactions greater than 2% (and higher than placebo) in COPD patients exposed to Infortispir Respimat 5 mcg: Pooled data from the four 48-week, double-blind, active- and placebo-controlled clinical trials in COPD patients 40 years of age and older

Additional adverse reactions that occurred in greater than 2% (and higher than placebo) of patients exposed to Infortispir Respimat 10 mcg were pneumonia, constipation, and pyrexia.

Lung cancers were reported in 6 (0.7%), 3 (0.3%), and 2 (0.2%) patients who received Infortispir Respimat 10 mcg, 5 mcg, and placebo, respectively.

The expected signs and symptoms with overdosage of Infortispir Respimat are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of Infortispir Respimat.

Treatment of overdosage consists of discontinuation of Infortispir Respimat together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Infortispir Respimat. Cardiac monitoring is recommended in cases of overdosage.

Systemic Safety

The major adverse effects of inhaled beta₂-adrenergic agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium, and increases in plasma glucose.

Changes in serum potassium were evaluated in COPD patients in double-blind phase 3 studies. In pooled data, at the recommended 5 mcg dose there was no clinically relevant change compared to placebo in serum potassium.

Electrophysiology

The effect of Infortispir Respimat on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomized, placebo- and active (moxifloxacin)-controlled study at single doses of 10, 20, 30, and 50 mcg. Dose-dependent QTcI (individual subject corrected QT interval) prolongation was observed. The maximum mean (one-sided 95% upper confidence bound) difference in QTcI from placebo after baseline correction was 2.5 (5.6) ms, 6.1 (9.2) ms, 7.5 (10.7) ms and 8.5 (11.6) ms following doses of 10, 20, 30 and 50 mcg, respectively.

The effect of 5 mcg and 10 mcg Infortispir Respimat on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled phase 3 trials. There were no dose-or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between Infortispir Respimat 5 mcg, 10 mcg, and placebo.

Olodaterol showed linear pharmacokinetics. On repeated once-daily inhalation steady-state of olodaterol plasma concentrations was achieved after 8 days, and the extent of exposure was increased up to 1.8-fold as compared to a single dose.

Absorption

Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.

Distribution

Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of [¹⁴C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.

Metabolism

Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta₂-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose.

Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.

Elimination

Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. However, the effective half-life at daily dose of 5 μg calculated from Cmax from COPD patients is 7.5 hours.

Following intravenous administration of [¹⁴C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after intravenous administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following intravenous and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5% to 7% of the dose.