Striverdi Respimat

Striverdi Respimat

olodaterol

Manufacturer:

Boehringer Ingelheim
Full Prescribing Info
Contents
Olodaterol.
Description
The STRIVERDI RESPIMAT is a soft mist inhaler delivering olodaterol solution for inhalation.
The delivered dose is 2.5 microgram olodaterol per puff (2 puffs comprise one medicinal dose) and is equivalent to 2.7 microgram olodaterol hydrochloride (INN=olodaterol).
The delivered dose is the dose which is available for the patient after passing the mouthpiece.
Excipients/Inactive Ingredients: Benzalkonium chloride, disodium edetate, water, purified, citric acid (anhydrous).
Action
Pharmacotherapeutic group: Long-acting beta2-adrenergic agonist. ATC code: not yet assigned.
Pharmacology: Pharmacodynamics: Mechanism of action: Olodaterol has a high affinity and high selectivity to the human beta2-adrenoceptor.
In vitro studies have shown that olodaterol has more than 219-fold greater agonist activity at beta2-adrenoceptors compared to beta1-adrenoceptors and 1622-fold greater agonist activity compared to beta3-adrenoceptors.
The compound exerts it's pharmacological effects by binding and activation of beta2-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.
Olodaterol has the pre-clinical profile of a long-acting selective beta2-adrenoceptor agonist (LABA) with a fast onset of action and a duration of action of at least 24 hours. Beta-adrenoceptors are divided into three subtypes, beta1-adrenoceptors predominantly expressed on cardiac smooth muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle and beta3-adrenoceptors predominantly expressed on adipose tissue. Beta2-agonists cause bronchodilation.
Although the beta2-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 beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.
Effects on cardiac electrophysiology: The effect of olodaterol on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomised, placebo- and active (moxifloxacin) controlled study. Olodaterol at single doses of 10, 20, 30 and 50 microgram, demonstrated that compared with placebo, the mean changes from baseline in QT interval over 20 minutes to 2 hours after dosing increased dose-dependently from 1.6 (10 microgram olodaterol) to 6.5 ms (50 microgram olodaterol), with the upper limit of the two-sided 90% confidence intervals being less than 10 ms at all dose levels.
The effect of 5 microgram and 10 microgram STRIVERDI 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 olodaterol 5 microgram, 10 microgram and placebo.
Clinical efficacy and safety: The Phase III clinical development program for STRIVERDI RESPIMAT included four pairs of replicate, randomised, double-blind, placebo-controlled trials in 3533 COPD patients (1281 received the 5 microgram dose, 1284 received the 10 microgram dose): (i) two replicate, placebo-controlled, parallel group, 48 week trials (Trials 1 and 2); (ii) two replicate, placebo- and active-controlled, parallel group, 48 week trials, with formoterol 12 microgram twice daily as active comparator (Trials 3 and 4); (iii) two replicate, placebo- and active-controlled, 6 week cross-over trials, with formoterol 12 microgram twice daily as active comparator (Trials 5 and 6); (iv) two replicate, placebo- and active-controlled, 6 week cross-over trials, with tiotropium HandiHaler 18 microgram once daily as active comparator (Trials 7 and 8).
All studies included lung function measurements (forced expiratory volume in one second, FEV1); the 48 weeks studies evaluated peak (AUC0-3) and trough lung function responses, while the 6 week studies evaluated the lung function profile over a continuous 24 hour dosing interval. The two replicate, placebo- and active-controlled, 48 week trials also included the Transition Dyspnoea Index (TDI) as a measure of dyspnoea and the St. George's Respiratory Questionnaire (SGRQ) as a measure of health-related quality of life.
Patients enrolled into the Phase III program were 40 years of age or older with a clinical diagnosis of COPD, had a smoking history of at least 10 pack years and had moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal (GOLD Stage II-IV); post-bronchodilator FEV1 to FVC ratio of less than 70%).
Patient characteristics: The majority of the 3104 patients recruited in the global, 48 week trials [Trials 1 and 2, Trials 3 and 4] were male (77%), white (66%) or Asian (32%), with a mean age of 64 years. Mean post-bronchodilator FEV1 was 1.38 L (GOLD II [50%], GOLD III [40%], GOLD IV [10%]). Mean β2-agonist responsiveness was 15% of baseline (0.160 L). With the exception of other long acting β2-agonists, all pulmonary medications were allowed as concomitant therapy (e.g. tiotropium [24%], ipratropium [25%], inhaled steroids [45%], xanthines [16%]); patient enrolment was stratified by tiotropium use. In all four trials, the primary lung function efficacy endpoints were change from pre-treatment baseline in FEV1 AUC0-3 and change from pre-treatment baseline in trough (pre-dose) FEV1 (after 12 weeks in Trials 1 and 2; after 24 weeks in Trials 3 and 4).
The 6 week trials [Trials 5 and 6, Trials 7 and 8] were conducted in Europe and North America. In Trials 5 and 6, the majority of the 199 recruited patients were male (53%) and white (93%), with a mean age of 63 years. Mean post-bronchodilator FEV1 was 1.43 L (GOLD II [54%], GOLD III [39%], GOLD IV [7%]). Mean β2-agonist responsiveness was 17% of baseline (0.187 L). With the exception of other long acting β2-agonists, all pulmonary medications were allowed as concomitant therapy (e.g. tiotropium [24%], ipratropium [16%], inhaled steroids [31%], xanthines [0.5%]). In Trials 7 and 8, the majority of the 230 recruited patients were male (69%) and white (99.6%), with a mean age of 62 years. Mean post-bronchodilator FEV1 was 1.55 L (GOLD II [57%], GOLD III [35%], GOLD IV [7%]). Mean β2-agonist responsiveness was 18% of baseline (0.203 L). With the exception of other long acting β2-agonists and anti-cholinergics, all pulmonary medications were allowed as concomitant therapy (e.g. inhaled steroids [49%], xanthines [7%]).
Lung function: In the 48 week trials, STRIVERDI RESPIMAT, 5 microgram administered once daily in the morning, provided significant improvement (p<0.0001) in lung function within 5 minutes following the first dose (mean 0.130 L increase in FEV1 compared with a pre-treatment baseline of 1.18 L). Significant improvement in lung function was maintained for 24 hours (mean 0.162 L increase in FEV1 AUC0-3 compared to placebo, p<0.0001; mean 0.071 L increase in 24 hour trough FEV1 compared to placebo, p<0.0001); the lung function improvements were evident in both tiotropium users and non-tiotropium users. The improvements in FEV1 AUC0-3 and trough FEV1 were comparable to twice daily formoterol. The bronchodilator effects of STRIVERDI RESPIMAT were maintained throughout the 48 week treatment period. STRIVERDI RESPIMAT also improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings compared to placebo.
In the 6 week trials, STRIVERDI RESPIMAT showed a significantly greater FEV1 response compared to placebo (p<0.0001) over the full 24 hour dosing interval (see Figure 1, Figure 2 and Table 1).


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Dyspnoea, Health-related Quality of Life, Rescue Medication Use, Patient Global Rating: The Transition Dyspnoea Index (TDI) and the St. George's Respiratory Questionnaire (SGRQ) were also included in the replicate, placebo- and active-controlled, 48 week trials [Trials 3 and 4]. After 24 weeks, there was no significant difference between STRIVERDI RESPIMAT, eformoterol and placebo in the TDI focal score (there was an unexpected improvement in the placebo group in one study) (see Table 2).


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After 24 weeks, STRIVERDI RESPIMAT significantly improved mean SGRQ total score compared to placebo; improvements were seen in all 3 SGRQ domains (symptoms, activities, impact) as shown in Table 3. More patients treated with STRIVERDI RESPIMAT had an improvement in SGRQ total score greater than the MCID (4 units) compared to placebo (50.2% vs. 36.4%), p<0.0001. (See Table 3.)


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Patients treated with STRIVERDI RESPIMAT used less daytime and nighttime rescue salbutamol compared to patients treated with placebo.
Exercise tolerance: The effect of STRIVERDI RESPIMAT on symptom-limited exercise tolerance in COPD patients was investigated in two replicate, randomised, double-blind, placebo- controlled, 6 week cross-over trials. In these trials, STRIVERDI RESPIMAT significantly improved exercise endurance time by 14.0% (p=0.0002) and 11.8% (p=0.0018) compared to placebo. STRIVERDI RESPIMAT also reduced lung hyperinflation (reduced functional residual capacity, FRC), resulting in increased inspiratory capacity at rest and during exercise compared to placebo.
In each of the 48 week trials, patients treated with STRIVERDI RESPIMAT perceived a greater improvement in their respiratory condition compared to placebo, as measured by a Patient's Global Rating (PGR) scale, providing further evidence of symptomatic benefit.
Pharmacokinetics: Information on the pharmacokinetics of olodaterol has been obtained from healthy subjects, COPD patients and asthma patients following oral inhalation of doses at and above the therapeutic dose.
Olodaterol showed linear pharmacokinetics with a dose-proportional increase of systemic exposure after single inhaled doses of 5 to 70 microgram and multiple once daily inhaled doses of 2 to 20 microgram.
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 is rapidly absorbed, reaching 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%.
Biotransformation: 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 (SOM 1522) binds to ß2-receptors; this metabolite however is not detectable in plasma after chronic inhalation of the recommended therapeutic dose or doses of up to 4-fold higher.
Olodaterol thus is considered the only compound relevant for pharmacological action.
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.
Following intravenous administration of [14C]-labelled 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 the radioactivity 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 5-7% of the dose.
Characteristics in Patients: A pharmacokinetic meta-analysis was performed utilizing data from 2 controlled clinical trials that included 405 patients with COPD and 296 patients with asthma who received treatment with STRIVERDI RESPIMAT.
The analysis showed that no dose adjustment is necessary based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of STRIVERDI RESPIMAT.
Renal Insufficiency: In subjects with severe renal impairment (CLCR <30 mL/min) [12] systemic exposure to olodaterol was on average 1.4-fold increased.
This magnitude of exposure increase does not raise any safety concerns given the safety experience of treatment with STRIVERDI RESPIMAT in clinical studies of up to one year at doses up to twice the recommended therapeutic dose.
Hepatic Insufficiency: In subjects with mild and moderate hepatic impairment systemic exposure to olodaterol was not affected. The effect of severe hepatic impairment on systemic exposure to olodaterol was not investigated.
Race: Comparison of pharmacokinetic data within and across studies revealed a trend for higher systemic exposure in Japanese and other Asians than in Caucasians.
No safety concerns were identified in clinical studies with Caucasians and Asians of up to one year with STRIVERDI RESPIMAT at doses up to twice the recommended therapeutic dose.
Drug-Drug Interactions: Drug-drug interaction studies were carried out using fluconazole as model inhibitor of CYP 2C9 and ketoconazole as potent P-gp and CYP inhibitor.
Fluconazole: Co-administration of 400 mg fluconazole once daily for 14 days had no relevant effect on systemic exposure to olodaterol.
Ketoconazole: Co-administration of 400 mg ketoconazole once daily for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.
Tiotropium: Co-administration of 5 microgram tiotropium bromide (delivered as fixed dose combination with 10 microgram olodaterol via the RESPIMAT) for 21 days had no relevant effect on systemic exposure to olodaterol, and vice versa.
Toxicology: Acute toxicity after single-dose inhalation, intravenous and oral-administration in mice and rats, was low.
The single-dose safety pharmacology studies showed the expected effects of a beta2-adrenergic agonist including decrease of blood pressure, increase in heart rate and force of contraction.
The effects in the inhalation repeat-dose studies in mice, rats and dogs were mainly related to beta2-adrenergic properties including increase in body weight and food consumption (rodents); increase in heart rate, changes in glycogen distribution in the liver, papillary muscle necrosis (dog).
In a inhalation repeat-dose study in juvenile dogs, doses of up to 1046 microgram/kg/day were well tolerated. No signs of impairment of lung or heart development were present.
In the rat, no teratogenic effects occurred after inhalation of doses up to 1054 microgram/kg/day (approximately 1600 times the maximum recommended human daily inhalation dose (MRHDID) in adults (5 microgram) on a mg/m2 basis). In pregnant NZW rabbits the administered inhalation dose of 2489 microgram/kg/day (exposure multiple versus the MRHDID of >3500 on AUC0-24) of olodaterol exhibited fetal toxicity characteristically resulting from beta-adrenoceptor stimulation; these included patchy ossifications, short/bent bones, partially open eye, cleft palate, cardiovascular abnormalities. No significant effects occurred at an inhalation dose of 974 microgram/kg (approximately 1580 times the MRHDID in adults on a m2 basis).
No impairment of male or female fertility or early embryonic development was seen in the rat up to inhalation doses of 3068 microgram/kg (approximately 3000 times the MRHDID in adults on a m² basis).
No effects were observed on mating, fertility or bearing of live implants to Day 14/15/16 of gestation in the F1 animals in the rat up to inhalation doses of 3665 microgram/kg/day (approximately 2970 times the MRHDID in adults on a m2 basis).
In in vivo rat bone marrow micronucleus assay after inhalation exposure (up to approximately 2000 times the MRHDID in adults on a m2 basis) and in vitro (Ames test, mouse lypmphoma assay) mutagenicity assays, olodaterol was free of any genotoxic potential up to very high dose levels. The increased frequency of micronuclei in rats at i.v. doses of at least 3500-times the MRHIDD was likely related to drug enhanced (compensatory) erythropoiesis. The mechanism for induction of micronuclei formation is likely not relevant at clinical exposures.
Inhalation carcinogenicity studies in mice and rats did not reveal any carcinogenic potential.
Lifetime treatment of rats induced class- and rodent-specific leiomyomas of the mesovarium at exposures approximately 2235-fold and 715-fold the exposure at the dose of 5 microgram once-daily for humans (on systemic exposure). Lifetime treatment of mice induced class- and rodent-specific smooth muscle tumours (leiomyomas, leiomyosarcomas) of the uterus and incidences of sex cord stromal focal hyperplasia and luteal focal hyperplasia in the ovary at exposures approximately 477- to 3596-fold the exposure at the dose of 5 microgram once-daily for humans (on systemic exposure), again considered as class- and rodent specific (exposure multiples). Both studies revealed no evidence for an olodaterol-related human risk with regard to carcinogenicity or chronic toxicity.
Genotoxicity: There was no evidence for genotoxicity of olodaterol in standard assays in vitro (bacterial reverse mutation, mammalian forward mutation) and in vivo rat bone marrow micronucleus assay after inhalational doses up to 1,360 microgram/kg/day for 4 weeks (plasma AUC 1,100 times the anticipated clinical exposure). An increased frequency of micronuclei in rats after single intravenous doses of 10 mg/kg or greater was likely related to drug enhanced (compensatory) erythropoiesis, and is unlikely to be relevant at clinical exposures.
Carcinogenicity: Lifetime treatment of rats induced class- and rodent-specific leiomyomas of the mesovarium at exposures approximately 213-fold the anticipated plasma AUC in adults at the dose of 5 microgram once daily. Lifetime treatment of mice induced class- and rodent-specific smooth muscle tumours (leiomyomas, leiomyosarcomas) of the uterus and incidences of sex cord stromal focal hyperplasia and luteal focal hyperplasia in the ovary at exposures approximately 40- to 400-fold the AUC in adults at the dose of 5 microgram once daily. These findings are not considered to indicate a carcinogenic hazard to patients.
Indications/Uses
STRIVERDI RESPIMAT is indicated as long-term once daily maintenance bronchodilator treatment to improve lung function in patients with COPD.
Dosage/Direction for Use
The recommended dose for adults is 5 microgram olodaterol given as two puffs from the RESPIMAT once-daily at the same time of the day. Do not use STRIVERDI RESPIMAT more than two inhalations every 24 hours (see Patient Counselling Information).
Elderly: Elderly patients can use STRIVERDI RESPIMAT at the recommended dose.
Paediatric population: COPD does not normally occur in children. The safety and effectiveness of STRIVERDI RESPIMAT in the pediatric population have not been established.
Patients with hepatic insufficiency: Patients with mild and morderate hepatic impairment can use STRIVERDI RESPIMAT at the recommended dose.
There are no data available for use of STRIVERDI RESPIMAT in patients with servere hepatic impairment.
Patients with renal insufficiency: Renally impaired patients can use STRIVERDI RESPIMAT at the recommended dose.
Overdosage
Symptoms: An overdose of olodaterol is likely to lead to exaggerated effects typical of beta2-adrenergic agonists, i.e. myocardial ischaemia, hypertension or hypotension, tachycardia, arrhythmias, palpitation, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.
Treatment of overdose: Treatment with STRIVERDI RESPIMAT should be discontinued. Supportive and symptomatic treatment is indicated. Serious cases should be hospitalised. Use of cardioselective beta-blockers may be considered, but only subject to extreme caution since the use of beta-adrenergic blocker medication may provoke bronchospasm.
Contraindications
STRIVERDI RESPIMAT is contraindicated in patients with hypersensitivity to olodaterol or to any of the excipients.
Special Precautions
Asthma: STRIVERDI RESPIMAT should not be used in asthma. The long-term effectiveness and safety of olodaterol in asthma have not been studied. Long-acting beta2-adrenergic agonists (LABA) may increase the risk of asthma-related hospitalisations and death.
Data from a large placebo-controlled study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including olodaterol, the active ingredient in STRIVERDI RESPIMAT.
Acute bronchospasm: STRIVERDI RESPIMAT is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy.
Hypersensitivity: As with all medications, immediate hypersensitivity reactions may occur after administration of STRIVERDI RESPIMAT.
Deterioration of disease and acute episodes: STRIVERDI RESPIMAT should not be initiated in patients with acutely deteriorating COPD. In this case, the patient's COPD management plan should direct the patient to seek medical advice immediately, and a re-evaluation of the patient and the COPD treatment regimen should be undertaken. Increasing the daily dosage of STRIVERDI RESPIMAT beyond the recommended dose is not appropriate.
Paradoxical bronchospasm: As with other Inhaled medicines STRIVERDI RESPIMAT may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs STRIVERDI RESPIMAT should be discontinued immediately and alternative therapy substituted.
Systemic effects: 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; 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.
Patients with a history of myocardial infarction during the previous year, unstable or life-threatening cardiac arrhythmia, hospitalized for heart failure during the previous year or with a diagnosis of paroxysmal tachycardia (>100 beats per minute) were excluded from the clinical trials. Therefore the experience in these patient groups is limited. STRIVERDI RESPIMAT should be used with caution in these patient groups.
Cardiovascular effects: Like other beta2-adrenergic agonists, olodaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave and ST segment depression, although the clinical significance of these observations is unknown.
Hypokalaemia: Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see Interactions), which may increase the susceptibility to cardiac arrhythmias.
Hyperglycaemia: Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.
STRIVERDI RESPIMAT should not be used in conjunction with any other medication containing long-acting beta2-adrenergic agonists.
Patients who have been taking inhaled, short acting beta2-adrenergic agonists on a regular basis (e.g. four times a day) should be instructed to use them only for symptomatic relief of acute respiratory symptoms.
Excipients: This medicine contains 0.0011 mg benzalkonium chloride in each actuation.
Benzalkonium chloride may cause wheezing and breathing difficulties. Patients with asthma are at an increased risk for these adverse events.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that dizziness has been reported in clinical trials. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.
Use In Pregnancy & Lactation
Pregnancy: For STRIVERDI RESPIMAT no clinical data on exposed pregnancies are available.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures.
As with any medicine, use during pregnancy should only be considered if the expected benefit to the mother is greater than any risk to the foetus.
The inhibitory effect of beta-adrenergic agonists on uterine contraction should be taken into account.
Lactation: Clinical data from nursing women exposed to olodaterol are not available.
The substance and/or its metabolites have been detected in the milk of lactating rats, but no adverse effects on development or reproductive performance were seen in breast-fed pups at maternal inhalational doses up to 3,665 microgram/kg/day (plasma AUC approximately 3,000 times the anticipated AUC in adults). It is not known whether olodaterol passes into human breast milk.
Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with STRIVERDI RESPIMAT should be made taking into account the benefit of breast-feeding to the child and the benefit of STRIVERDI RESPIMAT therapy to the woman.
Fertility: Clinical data on fertility are not available for STRIVERDI RESPIMAT. Preclinical studies performed with olodaterol showed no adverse effect on fertility (see Pharmacology: Toxicology under Actions).
No impairment of male or female fertility or early embryonic development was seen in the rat at inhalational doses up to approximately 3,000 microgram/kg/day (plasma AUC more than approximately 2,000 times the anticipated AUC in adults from a 5 microgram dose basis).
Side Effects
The safety of STRIVERDI RESPIMAT has been evaluated in placebo- and active-controlled, parallel-group and cross-over clinical trials in overall 4,167 patients with COPD. A total of 1,927 patients with COPD received the target dose of 5 microgram olodaterol.
Side effects of STRIVERDI RESPIMAT were primarily identified from data obtained in 4 placebo-controlled, parallel-group, long-term treatment (48 weeks) clinical trials in COPD patients. Two of these trials were also active-comparator controlled.
Infections and infestations: Nasopharyngitis, Upper respiratory tract infection, Bronchitis, Urinary tract infection.
Nervous system disorders: dizziness.
Vascular disorders: hypertension.
Skin and subcutaneous disorders: rash.
Musculoskeletal and connective tissue disorders: Arthralgia, Back pain.
Respiratory, thoracic, and mediastinal disorders: Cough.
Gastrointestinal disorders: Diarrhoea.
Occurrence of rash may be considered a hypersensitivity reaction with STRIVERDI RESPIMAT; as with all topical absorbed medication, other hypersensitivity reactions may develop.
Olodaterol is a member of the therapeutic class of long-acting beta2-adrenergic agonists. Therefore, the occurrence of undesirable effects related to the beta-adrenergic agonist class should be taken into consideration, such as tachycardia, arrhythmia, palpitations, myocardial ischaemia, angina pectoris, hypertension or hypotension, tremor, headache, nervousness, insomnia, dizziness, dry mouth, nausea, muscle spasms, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.
Drug Interactions
Concomitant administration of other adrenergic agents may potentiate the undesirable effects of STRIVERDI RESPIMAT.
Xanthine Derivatives, Steroids or Diuretics: Concomitant treatment with xanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate any hypokalemic effect of adrenergic agonists (see Precautions).
Beta-blockers: Beta-adrenergic blockers may weaken or antagonise the effect of STRIVERDI RESPIMAT. Therefore STRIVERDI RESPIMAT should only be given together with beta-adrenergic blockers (including eye-drops) if there are compelling reasons for their use.
In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
MAO Inhibitors, Tricyclic Antidepressants, QTc prolonging drugs: Monamine oxidase inhibitors, or tricyclic antidepressants or other drugs known to prolong the QTc interval may potentiate the action of STRIVERDI RESPIMAT on the cardiovascular system.
Pharmacokinetic Drug-Drug interactions: In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole a 1.7-fold increase of systemic exposure was observed (see Pharmacology: Pharmacokinetics under Actions).
No safety concerns were identified in clinical studies of up to one year with STRIVERDI RESPIMAT at doses up to twice the recommended therapeutic dose. No dose adjustment is necessary.
Storage
Store below 30°C. Do not freeze.
Store in a safe place, out of the reach of children.
Shelf life: 3 years.
In-use shelf-life: 3 months after the cartridge is inserted into the RESPIMAT inhaler.
Patient Counseling Information
STRIVERDI RESPIMAT is intended for oral inhalation only. The STRIVERDI RESPIMAT cartridge is only intended for use with the STRIVERDI RESPIMAT inhaler.
To ensure proper administration of STRIVERDI RESPIMAT, the patient should be shown how to use the STRIVERDI RESPIMAT inhaler by a physician or other health professional.
You will need to use this inhaler only ONCE A DAY. Each time you use it take TWO PUFFS.
How to care for your STRIVERDI RESPIMAT: Clean the mouthpiece including the metal part inside the mouthpiece with a damp cloth or tissue only, at least once a week.
Any minor discoloration in the mouthpiece does not affect your STRIVERDI RESPIMAT inhaler performance.
When to get a new STRIVERDI RESPIMAT: Your STRIVERDI RESPIMAT inhaler contains 60 puffs (30 doses) if used as indicated (two puffs/Once daily).
The dose indicator shows approximately how much medication is left.
When the dose indicator enters the red area of the scale you need to get a new prescription; there is approximately medication for 7 days left (14 puffs).
Once the dose indicator reaches the end of the red scale, your STRIVERDI RESPIMAT locks automatically - no more doses can be released. At this point, the clear base cannot be turned any further.
Three months after first use, the STRIVERDI RESPIMAT should be discarded even if it has not been used.
Prepare for first use: 1. Remove clear base: Keep the cap closed.
Press the safety catch while firmly pulling off the clear base with your other hand.
2. Insert cartridge: Insert the narrow end of the cartridge into the inhaler.
Place the inhaler on a firm surface and push down firmly until it snaps into place.
3. Replace clear base: Put the clear base back into place until it clicks.
4. Turn: Keep the cap closed.
Turn the clear base in the direction of the arrows on the label until it clicks (half a turn).
5. Open: Open the cap until it snaps fully open.
6. Press: Point the inhaler toward the ground.
Press the dose-release button.
Close the cap.
Repeat steps 4-6 until a cloud is visible.
After a cloud is visible, repeat steps 4-6 three more times.
Daily use: TURN: Keep the cap closed.
TURN the clear base in the direction of the arrows on the label until it clicks (half a turn).
OPEN: OPEN the cap until it snaps fully open.
PRESS: Breathe out slowly and fully.
Close your lips around the mouthpiece without covering the air vents.
While taking a slow, deep breath through your mouth, PRESS the dose-release button and continue to breathe in.
Hold your breath for 10 seconds or for as long as comfortable.
Repeat Turn, Open, Press for a total of 2 puffs.
ATC Classification
R03AC19 - olodaterol ; Belongs to the class of adrenergic inhalants, selective beta-2-adrenoreceptor agonists. Used in the treatment of obstructive airway diseases.
Presentation/Packing
Soln for inhalation 2.5 mcg/puff (1 inhaler + 1 cartridge) x 60 puffs x 1's.
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