Included as part of the PRECAUTIONS section.
Serious Asthma-Related Events – Hospitalizations,
- The safety and efficacy of STRIVERDI RESPIMAT in patients
with asthma have not been established. STRIVERDI RESPIMAT is not indicated for
the treatment of asthma [see CONTRAINDICATIONS].
- 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
- No study adequate to determine whether the rate of
asthma-related death is increased in patients treated with STRIVERDI RESPIMAT
has been conducted.
- Available data do not suggest an increased risk of death
with use of LABA in patients with COPD.
Deterioration Of Disease And Acute Episodes
STRIVERDI RESPIMAT should not be initiated in patients
with acutely deteriorating COPD, which may be a life-threatening condition.
STRIVERDI RESPIMAT has not been studied in patients with acutely deteriorating
COPD. The use of STRIVERDI RESPIMAT in this setting is inappropriate.
STRIVERDI RESPIMAT should not be used for the relief of acute
symptoms, i.e., as rescue therapy for the treatment of acute episodes of
bronchospasm. STRIVERDI 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 STRIVERDI 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 STRIVERDI 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 STRIVERDI 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 STRIVERDI RESPIMAT beyond the recommended dose is not appropriate in
Excessive Use Of STRIVERDI RESPIMAT And Use With Long-Acting
As with other inhaled drugs containing beta2-adrenergic
agents, STRIVERDI 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.
As with other inhaled beta2-agonists, STRIVERDI RESPIMAT
may produce paradoxical bronchospasm that may be life-threatening. If
paradoxical bronchospasm occurs, STRIVERDI RESPIMAT should be discontinued
immediately and alternative therapy instituted.
STRIVERDI 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, STRIVERDI 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,
STRIVERDI 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
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]. The decrease in
serum potassium is usually transient, not requiring supplementation. Inhalation
of high doses of beta2-adrenergic agonists may produce increases in plasma
In patients with severe COPD, hypokalemia may be
potentiated by hypoxia and concomitant treatment [see DRUG INTERACTIONS],
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 STRIVERDI RESPIMAT with the rates similar to those for
placebo controls. STRIVERDI RESPIMAT has not been investigated in patients
whose diabetes mellitus is not well controlled.
Immediate hypersensitivity reactions, including
angioedema, may occur after administration of STRIVERDI RESPIMAT. If such a
reaction occurs, therapy with STRIVERDI RESPIMAT should be stopped at once and
alternative treatment should be considered.
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 STRIVERDI RESPIMAT,
when used as monotherapy [without an inhaled corticosteroid], increase the risk
of serious asthma-related events, including asthma-related death. STRIVERDI
RESPIMAT is not indicated for the treatment of asthma.
Not For Acute Symptoms
STRIVERDI 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,
- Significant decrease in lung function as outlined by the
Instruct patients not to stop therapy with STRIVERDI
RESPIMAT without physician/provider guidance since symptoms may recur after
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 STRIVERDI 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 STRIVERDI
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.
Inform patients that STRIVERDI RESPIMAT can produce
paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm
occurs, patients should discontinue STRIVERDI RESPIMAT.
Inform patients that immediate hypersensitivity
reactions, including angioedema, may occur after administration of STRIVERDI
RESPIMAT. Advise patient to immediately discontinue STRIVERDI RESPIMAT and
consult a physician.
Instructions For Administering STRIVERDI RESPIMAT
It is important for patients to understand how to
correctly administer STRIVERDI RESPIMAT inhalation spray using the STRIVERDI
RESPIMAT inhaler. Instruct patients that STRIVERDI RESPIMAT inhalation spray
should only be administered via the STRIVERDI RESPIMAT inhaler and the
STRIVERDI RESPIMAT inhaler should not be used for administering other
Instruct patients that priming STRIVERDI RESPIMAT is
essential to ensure appropriate content of the medication in each actuation.
When using the unit for the first time, the STRIVERDI
RESPIMAT cartridge is inserted into the STRIVERDI RESPIMAT inhaler and the unit
is primed. STRIVERDI 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.
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
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
There are no adequate and well-controlled clinical
studies with STRIVERDI RESPIMAT in pregnant women to inform of drug-associated
risk of adverse pregnancy-related outcomes. There are clinical considerations
with the use of STRIVERDI RESPIMAT in pregnant women [see Clinical
Considerations]. 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 maximum recommended
human daily inhalation dose (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%,
Labor And Delivery
There are no adequate and well-controlled human studies
that have investigated the effects of STRIVERDI RESPIMAT during labor and
delivery. Because of the potential for beta-agonist interference with uterine
contractility, use of STRIVERDI RESPIMAT during labor should be restricted to
those patients in whom the benefits clearly outweigh the risks.
STRIVERDI RESPIMAT 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).
STRIVERDI RESPIMAT exhibited the following fetal toxicities: enlarged or small heart
atria or ventricles, eye abnormalities, and split or distorted sternum.
There are no available data on the presence of olodaterol
in human milk, the effects on the breastfed infant, or the effects on milk
production. Olodaterol, the active component of STRIVERDI RESPIMAT, and/or its
metabolites are present in the milk of lactating rats, however, due to
species-specific differences in lactation physiology, the clinical relevance of
these data are not clear [see Data]. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for STRIVERDI RESPIMAT and any potential adverse effects on the breastfed
child from STRIVERDI RESPIMAT or from the underlying maternal condition.
The distribution of olodaterol into milk was investigated
after a single intravenous administration of 0.4 μmol/kg to lactating
rats. Olodaterol and/or its metabolites are present in the milk of lactating
rats at concentrations above those in plasma.
STRIVERDI RESPIMAT is not indicated for use in children.
The safety and effectiveness of STRIVERDI RESPIMAT in the pediatric population
have not been established.
Based on available data, no adjustment of STRIVERDI
RESPIMAT dosage in geriatric patients is necessary.
Of the 876 patients who received STRIVERDI 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.
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.
Subjects with severe renal impairment showed no
clinically relevant changes in Cmax or AUC compared to their healthy controls.