tiotropium bromide 2.5 MCG / olodaterol 2.5 MCG per INHAL Metered Dose Inhaler, 60 ACTUAT
Generic Name: TIOTROPIUM BROMIDE AND OLODATEROL
Brand Name: Stiolto Respimat
- Substance Name(s):
- TIOTROPIUM BROMIDE MONOHYDRATE
- OLODATEROL HYDROCHLORIDE
DRUG INTERACTIONS
7 Other adrenergic drugs may potentiate effect.
Use with caution.
( 5.3 , 7.1 ) Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes.
Use with caution.
( 7.2 , 7.3 ) MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate effect on cardiovascular system.
Use with extreme caution.
( 7.4 ) Beta-blockers may decrease effectiveness.
Use with caution and only when medically necessary.
( 7.5 ) Anticholinergics: May interact additively with concomitantly used anticholinergic medications.
Avoid administration of STIOLTO RESPIMAT with other anticholinergic-containing drugs.
( 7.6 ) 7.1 Adrenergic Drugs If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of olodaterol, one component of STIOLTO RESPIMAT, may be potentiated [see Warnings and Precautions (5.3 , 5.6 , 5.10 , 5.11) ] .
7.2 Sympathomimetics, Xanthine Derivatives, Steroids, or Diuretics Tiotropium has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids, without increases in adverse reactions.
Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of olodaterol [see Warnings and Precautions (5.11) ] .
7.3 Non-Potassium Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Although the clinical significance of these effects is not known, caution is advised in the co-administration of STIOLTO RESPIMAT with non-potassium sparing diuretics.
7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs STIOLTO RESPIMAT, as with other drugs containing beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents.
Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias.
7.5 Beta-Blockers Beta-adrenergic receptor antagonists (beta-blockers) and the olodaterol component of STIOLTO RESPIMAT may interfere with the effect of each other when administered concurrently.
Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients.
Therefore, patients with COPD should not normally be treated with beta-blockers.
However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD.
In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
7.6 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medications.
Therefore, avoid co-administration of STIOLTO RESPIMAT with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.8 , 5.9) and Adverse Reactions (6) ] .
7.7 Inhibitors of Cytochrome P450 and P-gp Efflux Transporter In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol maximum plasma concentrations and AUC was observed [see Pharmacokinetics (12.3) ] .
Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose.
No dose adjustment of STIOLTO RESPIMAT is necessary.
OVERDOSAGE
10 STIOLTO RESPIMAT contains both tiotropium bromide and olodaterol; therefore, the risks associated with overdosage for the individual components described below apply to STIOLTO RESPIMAT.
Tiotropium High doses of tiotropium may lead to anticholinergic signs and symptoms.
However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers.
In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium.
Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, were observed following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.
Olodaterol The expected signs and symptoms with overdosage of olodaterol 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 olodaterol.
Treatment of overdosage consists of discontinuation of STIOLTO 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 STIOLTO RESPIMAT.
Cardiac monitoring is recommended in cases of overdosage.
DESCRIPTION
11 STIOLTO RESPIMAT is a combination of tiotropium, an anticholinergic, and olodaterol, a long-acting beta 2 -adrenergic agonist (LABA).
The drug substance tiotropium bromide monohydrate is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2,4 ] nonane bromide monohydrate.
It is a synthetic, non-chiral, quaternary ammonium compound.
Tiotropium bromide is a white or yellowish white powder.
It is sparingly soluble in water and soluble in methanol.
The structural formula is: Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C 19 H 22 NO 4 S 2 Br ∙ H 2 O.
The drug substance olodaterol hydrochloride is chemically described as 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]-amino]ethyl]-, monohydrochloride.
Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol.
The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C 21 H 26 N 2 O 5 × HCl as a hydrochloride.
The conversion factor from salt to free base is 1.094.
The structural formula is: The drug product, STIOLTO RESPIMAT, is composed of a sterile aqueous solution of tiotropium bromide and olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (STIOLTO RESPIMAT cartridge) for use with the STIOLTO RESPIMAT inhaler.
Excipients include water for injection, benzalkonium chloride, edetate disodium, and hydrochloric acid.
The STIOLTO RESPIMAT cartridge is only intended for use with the STIOLTO RESPIMAT inhaler.
The STIOLTO RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution.
The STIOLTO RESPIMAT inhaler has a light green-colored cap.
When used with the STIOLTO RESPIMAT inhaler each cartridge, containing 4 grams of sterile aqueous solution, delivers the labeled number of metered actuations after preparation for use.
Each dose (one dose equals two actuations) from the STIOLTO RESPIMAT inhaler delivers 5 mcg tiotropium and 5 mcg olodaterol in 22.1 mcL from the mouthpiece.
As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system.
The duration of inspiration should be at least as long as the spray duration (1.5 seconds).
Chemical Structure Chemical Structure
CLINICAL STUDIES
14 The safety and efficacy of STIOLTO RESPIMAT were evaluated in a clinical development program that included three dose ranging trials, two active-controlled trials, three active- and placebo-controlled trials, and one placebo-controlled trial.
The efficacy of STIOLTO RESPIMAT is based primarily on two 4-week dose-ranging trials in 592 COPD patients and two confirmatory active-controlled 52-week trials (Trials 1 and 2) in 5162 COPD patients.
Dose-Ranging Trials Dose selection for STIOLTO RESPIMAT was primarily based on trials for the individual components, tiotropium bromide and olodaterol.
Dose selection was also supported by two randomized, double-blind, active-controlled, 4-week trials.
In one trial in 232 patients with COPD, three tiotropium doses (1.25, 2.5, and 5 mcg) were given in combination with olodaterol 5 or 10 mcg and were evaluated compared to olodaterol monotherapy.
Results demonstrated improvement in trough FEV 1 for the combination when compared to olodaterol alone.
The difference in trough FEV 1 for the tiotropium bromide/olodaterol doses of 1.25/5, 2.5/5, and 5/5 mcg once daily from olodaterol 5 mcg were 0.054 L (95% CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084 L (0.046, 0.122), respectively.
In the second trial in 360 patients with COPD, three olodaterol doses (2, 5, and 10 mcg) were given in combination with tiotropium 5 mcg and were evaluated compared to tiotropium monotherapy.
The difference in trough FEV 1 for the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg once daily from tiotropium 5 mcg were 0.024 L (95% CI -0.029, 0.076), 0.033 L (-0.019, 0.085), and 0.057 L (0.004, 0.110), respectively.
Results of these trials supported the evaluation of once-daily doses of tiotropium bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.
Confirmatory Trials A total of 5162 COPD patients (1029 receiving STIOLTO RESPIMAT, 1038 receiving olodaterol 5 mcg, and 1033 receiving tiotropium bromide 5 mcg) were studied in two confirmatory trials of STIOLTO RESPIMAT.
Trials 1 and 2 were 52-week, replicate, randomized, double-blind, active controlled, parallel group trials that compared STIOLTO RESPIMAT to tiotropium 5 mcg and olodaterol 5 mcg.
In these trials, all products were administered via the RESPIMAT inhaler.
The trials enrolled patients 40 years of age or older with a clinical diagnosis of COPD, a smoking history of more than 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV 1 less than 80% predicted normal [GOLD Stage 2-4]; post-bronchodilator FEV 1 to FVC ratio of less than 70%).
All treatments were administered once daily in the morning.
The primary endpoints were change from baseline in FEV 1 AUC 0-3hr and trough FEV 1 after 24 weeks of treatment.
The majority of the 5162 patients were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years.
Mean post-bronchodilator FEV 1 was 1.37 L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]).
Mean beta 2 -agonist responsiveness was 16.6% of baseline (0.171 L).
Pulmonary medications allowed as concomitant therapy included inhaled steroids [47%] and xanthines [10%].
In both Trials 1 and 2, STIOLTO RESPIMAT demonstrated significant improvements in FEV 1 AUC 0-3hr and trough FEV 1 after 24 weeks compared to tiotropium 5 mcg and olodaterol 5 mcg (Table 2).
The increased bronchodilator effects of STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained throughout the 52-week treatment period.
STIOLTO RESPIMAT displayed a mean increase in FEV 1 from baseline of 0.137 L (range: 0.133-0.140 L) within 5 minutes after the first dose.
Patients treated with STIOLTO RESPIMAT used less rescue medication compared to patients treated with tiotropium 5 mcg and olodaterol 5 mcg.
Table 2 FEV 1 AUC 0-3hr and Trough FEV 1 response for STIOLTO RESPIMAT compared to tiotropium 5 mcg and olodaterol 5 mcg after 24 weeks (primary endpoints; Trials 1 and 2) Trial 1 Trial 2 n Mean (L) Difference (L) (95% CI) n Mean (L) Difference (L) (95% CI) Pre-treatment baseline FEV 1 : Trial 1=1.16 L; Trial 2=1.15 L p≤0.0001 for all comparisons between STIOLTO RESPIMAT and the monotherapies.
FEV 1 AUC 0-3hr response STIOLTO RESPIMAT 522 0.256 – 502 0.268 – Tiotropium 5 mcg 526 0.139 0.117 (0.094, 0.140) 500 0.165 0.103 (0.078, 0.127) Olodaterol 5 mcg 525 0.133 0.123 (0.100, 0.146) 507 0.136 0.132 (0.108, 0.157) Trough FEV 1 response STIOLTO RESPIMAT 521 0.136 – 497 0.145 – Tiotropium 5 mcg 520 0.065 0.071 (0.047, 0.094) 498 0.096 0.050 (0.024, 0.075) Olodaterol 5 mcg 519 0.054 0.082 (0.059, 0.106) 503 0.057 0.088 (0.063, 0.113) For the subset of patients (n=521) who completed extended lung function measurements up to 12 hours post-dose, STIOLTO RESPIMAT showed a significantly greater FEV 1 response compared to tiotropium 5 mcg and olodaterol 5 mcg over the full 24-hour dosing interval.
Results from Trial 2 are shown in Figure 1.
Figure 1 FEV 1 profile for STIOLTO RESPIMAT, tiotropium 5 mcg and olodaterol 5 mcg over a 24-hour dosing interval after 24 weeks (12 hr PFT subset from Trial 2) The St.
George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2 and in two additional 12-week placebo-controlled trials (Trials 3 and 4).
In the first 12-week trial, SGRQ responder rates at week 12 (defined as an improvement in score of 4 or more as a threshold) were 53%, 42%, and 31% for STIOLTO RESPIMAT, tiotropium 5 mcg, and placebo, respectively, with odds ratios of 1.6 (95% CI 1.1, 2.4) and 2.5 (95% CI 1.6, 3.8) for STIOLTO RESPIMAT vs.
tiotropium 5 mcg and STIOLTO RESPIMAT vs.
placebo, respectively.
In the second 12-week trial, results were similar with odds ratios of 1.5 (95% CI 1.0, 2.3) and 2.2 (95% CI 1.5, 3.4) for STIOLTO RESPIMAT vs.
tiotropium 5 mcg and STIOLTO RESPIMAT vs.
placebo, respectively.
For the 52-week trials similar responder rates were seen.
In Trial 1, the odds ratios for STIOLTO vs.
tiotropium 5 mcg and STIOLTO vs.
olodaterol 5 mcg at week 24 were 1.6 (95% CI 1.2, 2.0) and 1.9 (95% CI 1.5, 2.4), respectively.
The results were similar in the 52-week Trial 2, with odds ratios for STIOLTO vs.
tiotropium 5 mcg and STIOLTO vs.
olodaterol 5 mcg of 1.3 (95% CI 1.0, 1.7) and 1.5 (95% CI 1.1, 1.9), respectively.
Exacerbations Tiotropium 5 mcg Trials Evaluating Exacerbations The effect of tiotropium 5 mcg inhalation spray on exacerbations was evaluated in three 48-week randomized, double-blind, placebo-controlled clinical trials that included COPD exacerbations as the primary endpoint.
Exacerbations of COPD were defined as a complex of lower respiratory events/symptoms (increase or new onset) related to the underlying COPD, with duration of three days or more, requiring a prescription of antibiotics and/or systemic steroids and/or hospitalization.
In a pooled analysis of the first two trials, tiotropium 5 mcg significantly reduced the number of COPD exacerbations compared to placebo with a rate ratio of 0.78 (95% CI 0.67, 0.92).
In the third trial, tiotropium 5 mcg delayed the time to first COPD exacerbation compared to placebo with a hazard ratio of 0.69 (95% CI 0.63, 0.77).
STIOLTO RESPIMAT Trial Evaluating Exacerbations In a one-year, randomized, double-blind, active-controlled parallel group clinical trial (Trial 5), the effect of STIOLTO RESPIMAT on COPD exacerbations was compared with tiotropium 5 mcg inhalation spray.
Exacerbations were defined as above.
Enrolled patients (3939 patients receiving STIOLTO RESPIMAT and 3941 patients receiving tiotropium 5 mcg inhalation spray) had a history of COPD exacerbation in the previous 12 months.
The primary endpoint was the annualized rate of moderate to severe COPD exacerbations.
The majority of patients were male (71%) and Caucasian (79%).
The mean age was 66 years, and mean post-bronchodilator FEV 1 percent predicted was 45%.
STIOLTO RESPIMAT treatment did not demonstrate superiority to tiotropium 5 mcg inhalation spray for the primary endpoint, the annualized rate of moderate to severe COPD exacerbations, with a rate ratio of 0.93 (99% CI, 0.85-1.02, p=0.0498).
The study did not reach the pre-specified significance level of 0.01.
Figure 1
HOW SUPPLIED
16 /STORAGE AND HANDLING STIOLTO RESPIMAT Inhalation Spray is supplied in a labeled carton containing one STIOLTO RESPIMAT cartridge and one STIOLTO RESPIMAT inhaler.
The STIOLTO RESPIMAT cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap.
The STIOLTO RESPIMAT cartridge is only intended for use with the STIOLTO RESPIMAT inhaler and should not be interchanged with any other RESPIMAT device delivered product.
The STIOLTO RESPIMAT inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base.
The clear base is removed to insert the cartridge.
The inhaler contains a dose indicator.
The light green-colored cap and the written information on the label of the gray inhaler body indicate that it is labeled for use with the STIOLTO RESPIMAT cartridge.
STIOLTO RESPIMAT Inhalation Spray is available as: STIOLTO RESPIMAT Inhalation Spray: 60 metered actuations (NDC 0597-0155-61) STIOLTO RESPIMAT Inhalation Spray: 10 metered actuations (NDC 0597-0155-70) (institutional pack) The STIOLTO RESPIMAT cartridge has a net fill weight of at least 4 grams and when used with the STIOLTO RESPIMAT inhaler, is designed to deliver the labeled number of metered actuations after preparation for use.
When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.
After assembly, the STIOLTO RESPIMAT inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.
Keep out of reach of children.
Do not spray into eyes.
Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Avoid freezing.
GERIATRIC USE
8.5 Geriatric Use Based on available data, no adjustment of STIOLTO RESPIMAT dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3) ].
Of the 1029 patients who received STIOLTO RESPIMAT at the recommended dose once daily in the clinical studies from the pooled 1-year database, 525 (51.0%) were <65 years of age, 407 (39.6%) were 65 to <75, 96 (9.3%) were 75 to <85, and 1 (0.1%) was ≥85.
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.
DOSAGE FORMS AND STRENGTHS
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.
( 3 ) Inhalation Spray: STIOLTO RESPIMAT consists of a STIOLTO RESPIMAT inhaler and an aluminum cylinder (STIOLTO RESPIMAT cartridge) containing a combination of tiotropium bromide (as the monohydrate) and olodaterol (as the hydrochloride).
The STIOLTO RESPIMAT cartridge is intended only for use with the STIOLTO RESPIMAT inhaler.
Each actuation from the STIOLTO RESPIMAT inhaler 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) from the mouthpiece.
Two actuations equal one dose.
MECHANISM OF ACTION
12.1 Mechanism of Action STIOLTO RESPIMAT STIOLTO RESPIMAT contains both tiotropium and olodaterol.
The properties described below for the individual components apply to STIOLTO RESPIMAT.
These drugs represent 2 different classes of medication (an anticholinergic and a beta-agonist) that have different effects on clinical and physiological indices.
Tiotropium Tiotropium is a long-acting, muscarinic antagonist which is often referred to as an anticholinergic.
It has similar affinity to the subtypes of muscarinic receptors, M 1 to M 5 .
In the airways, it exhibits pharmacological effects through inhibition of M 3 -receptors 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 methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours.
The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.
Olodaterol Olodaterol is a long-acting beta 2 -adrenergic agonist (LABA).
The compound exerts its pharmacological effects by binding and activation of beta 2 -adrenoceptors after topical administration by inhalation.
Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3′, 5′ adenosine monophosphate (cAMP).
Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells.
In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta 2 -adrenoceptors compared to beta 1 -adrenoceptors and 2299-fold greater agonist activity compared to beta 3 -adrenoceptors.
The clinical significance of these findings is unknown.
Beta-adrenoceptors are divided into three subtypes: beta 1 -adrenoceptors predominantly expressed on cardiac muscle, beta 2 -adrenoceptors predominantly expressed on airway smooth muscle, and beta 3 -adrenoceptors predominantly expressed on adipose tissue.
Beta 2 -agonists cause bronchodilation.
Although the beta 2 -adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle, it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart.
The precise function of beta 2 -receptors in the heart is not known, but their presence raises the possibility that even highly selective beta 2 -agonists may have cardiac effects.
INDICATIONS AND USAGE
1 STIOLTO RESPIMAT is a combination of tiotropium, an anticholinergic and olodaterol, a long-acting beta 2 -adrenergic agonist (LABA) indicated for the long-term, once-daily maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).
( 1.1 ) Important limitations: STIOLTO RESPIMAT is NOT indicated to treat acute deterioration of COPD.
( 1.1 ) STIOLTO RESPIMAT is NOT indicated to treat asthma.
( 1.1 ) 1.1 Maintenance Treatment of COPD STIOLTO RESPIMAT is a combination of tiotropium 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.
PEDIATRIC USE
8.4 Pediatric Use COPD does not normally occur in children.
The safety and effectiveness of STIOLTO RESPIMAT in the pediatric population has not been established.
PREGNANCY
8.1 Pregnancy Risk Summary There are no adequate and well-controlled clinical studies with STIOLTO RESPIMAT or its individual components, tiotropium bromide and olodaterol, in pregnant women to inform of drug-associated risk of adverse pregnancy-related outcomes.
Animal reproduction studies were conducted with the individual components of STIOLTO RESPIMAT, tiotropium bromide and olodaterol.
There are clinical considerations with the use of STIOLTO RESPIMAT in pregnant women [see Clinical Considerations ] .
STIOLTO RESPIMAT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 [see Data ] .
Based on animal studies, olodaterol was not teratogenic when administered to pregnant rats or rabbits during organogenesis at inhalation doses of approximately 2731 or 1353 times the MRHDID (on an AUC basis), in rats or rabbits, respectively [see Data ] .
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 Labor and Delivery There are no adequate and well-controlled human studies that have investigated the effects of STIOLTO RESPIMAT on preterm labor or labor at term.
Because of the potential for beta-agonist interference with uterine contractility, use of STIOLTO RESPIMAT during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
Data Animal Data Animal reproduction studies with the combination of tiotropium and olodaterol are not available; however, studies are available with the individual components.
Tiotropium 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 MRHDID, respectively (on a mcg/m 2 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/m 2 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/m 2 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/m 2 basis at inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).
Olodaterol Olodaterol was not teratogenic in rats at inhalation doses approximately 2731 times the MRHDID (on an AUC basis at a maternal inhalation dose of 1054 mcg/kg/day).
No significant effects occurred in rabbits at inhalation doses approximately 1353 times the MRHDID in adults (on an AUC basis at a maternal inhalation dose of 974 mcg/kg/day).
Placental transfer of olodaterol was observed in pregnant rats.
Olodaterol has been shown to be teratogenic in New Zealand rabbits at inhalation doses approximately 7130 times the MRHDID in adults (on an AUC basis at a maternal inhalation dose of 2489 mcg/kg/day).
Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events.
( 5.1 ) Do not initiate STIOLTO RESPIMAT in acutely deteriorating COPD patients.
( 5.2 ) Do not use for relief of acute symptoms.
Concomitant short-acting beta 2 -agonists can be used as needed for acute relief.
( 5.2 ) Do not exceed the recommended dose.
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 ) 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 ) Life-threatening paradoxical bronchospasm can occur.
Discontinue STIOLTO RESPIMAT immediately.
( 5.5 ) Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or sensitivity to sympathomimetic drugs.
( 5.6 , 5.7 ) 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 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 ) Be alert to hypokalemia and hyperglycemia.
( 5.11 ) 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 beta 2 -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.
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 beta 2 -agonist.
When beginning STIOLTO RESPIMAT, patients who have been taking inhaled, short-acting beta 2 -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 beta 2 -agonist and instruct the patient on how it should be used.
Increasing inhaled beta 2 -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 beta 2 -agonist becomes less effective or the patient needs more inhalation of short-acting beta 2 -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 dose is not appropriate in this situation.
5.3 Excessive Use of STIOLTO RESPIMAT and Use With Other Long-Acting Beta 2 -Agonists As with other inhaled drugs containing beta 2 -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 beta 2 -agonists, as an overdose may result.
Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
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.
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.
5.6 Cardiovascular Effects Olodaterol, like other beta 2 -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 beta 2 -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 beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.
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.
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.
5.10 Renal Impairment Because tiotropium is a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with STIOLTO RESPIMAT should be monitored closely for anticholinergic side effects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .
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 beta 2 -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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Serious Asthma-Related Events Inform patients that LABA, such as STIOLTO RESPIMAT, when used as monotherapy [without an inhaled corticosteroid], increase the risk of serious asthma-related events, including asthma-related death.
STIOLTO RESPIMAT is not indicated for the treatment of asthma.
Not for Acute Symptoms STIOLTO 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 beta 2 -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 beta 2 -agonists Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists Significant decrease in lung function as outlined by the physician Instruct patients not to stop therapy with STIOLTO RESPIMAT without physician/provider guidance since symptoms may recur after discontinuation.
Do Not Use Additional Long-Acting Beta 2 -Agonists Patients who have been taking inhaled, short-acting beta 2 -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 STIOLTO RESPIMAT, other inhaled medications containing long-acting beta 2 -agonists should not be used.
Patients should not use more than the recommended once-daily dose of STIOLTO RESPIMAT.
Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
Risks Associated with Beta 2 -Agonist Therapy Inform patients of adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
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 STIOLTO RESPIMAT.
Advise patient to immediately discontinue treatment and consult a physician should any of these signs or symptoms develop.
Paradoxical Bronchospasm Inform patients that STIOLTO RESPIMAT can produce paradoxical bronchospasm.
Advise patients that if paradoxical bronchospasm occurs, patients should discontinue STIOLTO RESPIMAT.
Urinary Retention Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction.
Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
Visual Effects Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma.
Inform patients to consult a physician immediately should any of these signs and symptoms develop.
Advise patients that miotic eye drops alone are not considered to be effective treatment.
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 STIOLTO RESPIMAT, caution patients about engaging in activities such as driving a vehicle or operating appliances or machinery.
Instructions for Administering STIOLTO RESPIMAT It is important for patients to understand how to correctly administer STIOLTO RESPIMAT inhalation spray using the STIOLTO RESPIMAT inhaler.
Instruct patients that STIOLTO RESPIMAT inhalation spray should only be administered via the STIOLTO RESPIMAT inhaler and the STIOLTO RESPIMAT inhaler should not be used for administering other medications.
Instruct patients that priming STIOLTO RESPIMAT is essential to ensure appropriate content of the medication in each actuation.
When using the unit for the first time, the STIOLTO RESPIMAT cartridge is inserted into the STIOLTO RESPIMAT inhaler and the unit is primed.
STIOLTO RESPIMAT 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 .
DOSAGE AND ADMINISTRATION
2 For oral inhalation only.
Two inhalations of STIOLTO RESPIMAT once-daily at the same time of day.
( 2 ) 2.1 Recommended Dosage The recommended dose 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) ] .