Stiolto Respimat

STIOLTO RESPIMAT is a combination of tiotropium bromide, an anticholinergic and olodaterol, a long-acting beta₂-adrenergic agonist (LABA) indicated for the long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). (

Important limitations:

• STIOLTO RESPIMAT is NOT indicated to treat acute deterioration of COPD. (
  1.1 Maintenance Treatment of COPD

  STIOLTO RESPIMAT is a combination of tiotropium bromide and olodaterol indicated for long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

  Important Limitations of Use

  • STIOLTO RESPIMAT is not indicated to treat acute deteriorations of COPD
    [see Warnings and Precautions (5.2)].
  • STIOLTO RESPIMAT is not indicated to treat asthma. The safety and effectiveness of STIOLTO RESPIMAT in asthma have not been established.
  )
• STIOLTO RESPIMAT is NOT indicated to treat asthma. (
  1.1 Maintenance Treatment of COPD

  STIOLTO RESPIMAT is a combination of tiotropium bromide and olodaterol indicated for long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

  Important Limitations of Use

  • STIOLTO RESPIMAT is not indicated to treat acute deteriorations of COPD
    [see Warnings and Precautions (5.2)].
  • STIOLTO RESPIMAT is not indicated to treat asthma. The safety and effectiveness of STIOLTO RESPIMAT in asthma have not been established.
  )

• For oral inhalation only.
• Two inhalations of STIOLTO RESPIMAT once-daily at the same time of day. (
  2 DOSAGE AND ADMINISTRATION

  • For oral inhalation only.
  • Two inhalations of STIOLTO RESPIMAT once-daily at the same time of day.

  2.1 Recommended Dosage

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

  2.2 Administration Information

  For oral inhalation only.

  Prior to first use, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO 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

  [see Patient Counseling Information (17)]

  .

  No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given STIOLTO RESPIMAT should be monitored closely for anticholinergic effects

  [see Warnings and Precautions (5.10), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3)]

  .
  )

Inhalation spray: Each actuation from the mouthpiece delivers 2.5 mcg tiotropium (equivalent to 3.124 mcg tiotropium bromide monohydrate), and 2.5 mcg olodaterol (equivalent to 2.736 mcg olodaterol hydrochloride). Two actuations equal one dose. (

Patients with moderate to severe renal impairment should be monitored closely for potential anticholinergic side effects. (

• LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. (
  5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

  • The safety and efficacy of STIOLTO RESPIMAT in patients with asthma have not been established. STIOLTO RESPIMAT is not indicated for the treatment of asthma
    [see Contraindications (4)]
    .
  • Use of long-acting beta₂-adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.
  • A 28-week, placebo-controlled US study comparing the safety of another LABA (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 LABA, including olodaterol, one of the active ingredients in STIOLTO RESPIMAT.
  • No study adequate to determine whether the rate of asthma-related death is increased in patients treated with STIOLTO RESPIMAT has been conducted.
  • Available data do not suggest an increased risk of death with use of LABA in patients with COPD.
  )
• Do not initiate STIOLTO RESPIMAT in acutely deteriorating COPD patients. (
  5.2 Deterioration of Disease and Acute Episodes

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

  STIOLTO RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STIOLTO 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 STIOLTO 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 STIOLTO 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 STIOLTO 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 STIOLTO RESPIMAT beyond the recommended dosage is not appropriate in this situation.
  )
• Do not use for relief of acute symptoms. Concomitant short-acting beta₂-agonists can be used as needed for acute relief. (
  5.2 Deterioration of Disease and Acute Episodes

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

  STIOLTO RESPIMAT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. STIOLTO 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 STIOLTO 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 STIOLTO 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 STIOLTO 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 STIOLTO RESPIMAT beyond the recommended dosage is not appropriate in this situation.
  )
• Do not exceed the recommended dosage. Excessive use of STIOLTO RESPIMAT, or use in conjunction with other medications containing LABA can result in clinically significant cardiovascular effects and may be fatal. (
  5.3 Excessive Use of STIOLTO RESPIMAT and Use With Other Long-Acting Beta₂-Agonists

  As with other inhaled drugs containing beta₂-adrenergic agents, STIOLTO 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.
  )
• Immediate hypersensitivity reactions: Discontinue STIOLTO RESPIMAT at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, urticaria, rash, bronchospasm, or anaphylaxis, occur. (
  5.4 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 STIOLTO RESPIMAT. If such a reaction occurs, therapy with STIOLTO RESPIMAT 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 STIOLTO RESPIMAT.
  )
• Life-threatening paradoxical bronchospasm can occur. Discontinue STIOLTO RESPIMAT immediately. (
  5.5 Paradoxical Bronchospasm

  As with other inhaled medicines, STIOLTO RESPIMAT may cause paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, STIOLTO RESPIMAT should be stopped immediately and alternative therapy instituted.
  )
• Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or sensitivity to sympathomimetic drugs. (
  5.6 Cardiovascular Effects

  Olodaterol, 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, STIOLTO 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.
  ,
  5.7 Coexisting Conditions

  Olodaterol, 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.
  )
• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (
  5.8 Worsening of Narrow-Angle Glaucoma

  STIOLTO RESPIMAT 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 may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. (
  5.9 Worsening of Urinary Retention

  STIOLTO RESPIMAT 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), 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.
  )
• Be alert to hypokalemia and hyperglycemia. (
  5.11 Hypokalemia and Hyperglycemia

  Beta-adrenergic agonists may produce significant hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects

  [see Clinical Pharmacology (12.2)]

  . 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

  [see Drug Interactions (7.2)]

  , 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 olodaterol with the rates similar to those for placebo controls. Olodaterol has not been investigated in patients whose diabetes mellitus is not well controlled.
  )