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Home , Formoterol, Salmeterol

06 2015 / drug assessment Anoro® for COPD report www.dtb.navarra.es No additions to efficacy, just to price @DTB_Navarre.es

abstract Indications3 dary variable,the Transition Dyspnea Index (TDI) Umeclidinium/vilanterol is a It is indicated as maintenance which measures the impact of dyspnea on daily combination of a muscarinic treatment to relieve the symptoms of chronic obs- life of patients and where 1 point is considered antagonist and a long acting b2 tructive pulmonary disease (COPD) in adults. as the minimum difference of clinical relevance. agonist. Nor were there statistically significant differences Mechanism of action3 found when compared to placebo or the indivi- No reduction in the risk of exa- Umeclidinium is a long acting muscarinic recep- dual components with regard to either quality of cerbations has been shown. tor antagonist (LAMA) that blocks the action of life evaluated through the St. George Respiratory acetylcholine in smooth muscle cells producing Questionnaire (SGRQ) or the risk of exacerbations. bronchodilation. Vilanterol is a selective long ac- It does not improve clinical re- ting b2 adrenoceptor agonist (LABA) that produces sults compared to tiotropium. relaxation of bronchial smooth muscle and the inhi- bition of the release of immediate hypersensitivity Vilanterol has not shown The role and contribution of vi- mediators. lanterol to the combination is not to improve efficacy clear. Posology and form of adminstration3 The recommended dose is one inhalation per day There are no comparative data using the dry powder (Ellipta®), for an inspi- available with respect to other ratory flow of 60ml/min for 4 seconds, providing a Three trials comparing umeclidinium/vilanterol LAMA+LABA combinations. release dose of 55mcg of umeclidinium and 22mcg with tiotropium, one of them also compares vilan- of vilanterol which correspond to pre-dispensed terol. Its cardiovascular safety profile doses of 62.5mcg and 25mcg respectively. It should In the DB2113360 y DB2113374 studies compa- is still a concern. be applied at the same time every day. ring the umeclidinium/vilanterol combination with tiotropium did not show statistically significant di- Comparators fferences in regard to TDI, SGRQ or in the use of LABA and LAMA individually or in combination. rescue medication. CLASSIFICATION In the ZEP117115 study, when comparing the Clinical efficacy4,5 combination to tiotropium statistically significant The clinical development program included trials differences were observed though they were not IMPORTANT which compared the authorized doses to placebo clinically relevant in terms of SGRQ (-2.10; 95%CI THERAPEUTIC or monotherapy. The primary endpoint was change -3.61 to -0.59; the minimum difference for clinical 4 INNOVATION with respect to initial values in Forced Expiratory relevance is 4) and the use of rescue treatment (0.5

Volume in 1 second (FEV1). The minimum value inhalations less per day; 95% CI 0.2 – 0.7). MODEST THERAPEUTIC considered clinically relevant is a difference of Two small cross over studies whose main ob- INNOVATION 100ml. The main trial compared umeclidinium/ jective was to evaluate the effect on resistance to 3 vilanterol with individual components separately exercise and lung function after 12 weeks showed SOME ADDED (ie: umeclidinium alone and vilanterol alone) and inconsistent results. In one of them, neither statisti- VALUE IN SPECIFIC with placebo. COPD patients included adults with ≥ cally significant results nor clinical relevance were 2 SITUATIONS 40 years (the average age was 63 years) with a his- found when comparing the combination to placebo tory of smoking of 10 or more packets/year, a post- or to the individual components. In the other, there NO THERAPEUTIC bronchodilator FEV1 of 70% or less the predicted was a statistically significant improvement of 69.4 INNOVATION value, and a score of ≥2 on the dyspnea mMRC seconds in walking time with respect to placebo. 1 scale. Patients with uncontrolled cardiovascular There are no studies lasting longer than 24 weeks. INSUFFICIENT disease were excluded. No studies are available comparing other LABA/ EVIDENCE The differences with umeclidinium were not cli- LAMA or combinations of LABA and corticoids. 0 nically relevant while in the case of vilanterol the clinical relevance of the differences observed is Safety doubtful. No statistically significant differences Adverse reactions were found when comparing umeclidinium/vilan- Nasopharyngitis was the most frequently repor- terol and its individual components in the secon- ted adverse effect. Other frequent adverse effects

Comparative Primary endpoint: Secundary endpoints: TDI The qualification assigned to the drug was agreed by the Drug Assessment Commit- treatments FEV1 after 24 weeks Difference between treatments (95% CI) Limit for clinical relevance: 1 point tees of Andalusia, Basque Country, Catalonia Difference between treatments (95% CI) Institute of Health, Aragon and Navarre. The Limit for clinical relevance: 100 ml current report is based on the available infor- UMEC/VI 62.5/25 versus placebo 167 ml (128 a 207 ml) 1.2 (0.7; 1.7) mation and is susceptible to be updated ac- cording to the latest evidence. Let us remind UMEC/VI 62.5/25 versus VI 25 95 ml (60 a 130 ml) 0.4 (-0.1; 0.8) the reader about the importance of notifying UMEC/VI 62.5/25 versus UMEC 62.5 52 ml (17 a 87 ml) 0.3 (-0.2; 0.7) the Pharmacovigilance Centre when there are suspicions of adverse reactions to drugs. Comparative treatments Principal endpoint: FEV1 after 24 weeks Place in therapeutics UMEC/VI 62.5/25 vs TIO 18 DB2113360 study DB2113374 study ZEP117115 study Inhaled such as long acting beta-2 adrenergic agonists (LABA) and long 90 ml (39 - 141 ml) 60 ml 112 ml (81 - 154 ml) No statistical significance acting anti-muscarinic antagonists (LAMA) can be inferred constitute the basis of symptomatic treatment UMEC/VI 62.5/25 versus VI 25 90 ml (39 - 142 ml) of patients with COPD and permanent symp- toms. The GOLD guidelines do not include the LAMA/LABA combination without corticoid as (incidence ≥1%) include , pharyngitis, in breast milk is unknown. Renal failure: No a recommended first choice for the manage- upper respiratory tract infections , dose adjustments are necessary. Liver failu- ment in any of the patient groups.1 oropharyngeal pain, dry mouth, urinary infec- re: no dose adjustments are required in case Umeclidinium/vilanterol is a LAMA/LABA tion, cefalea and constipation. Less frequent of mild and moderate liver dysfunction. The- combination that has only shown statistically adverse effects (incidence <1%) included re are no studies in patients with severe liver significant differences in variables that eva- atrial fibrillation, supraventricular tachycardia, failure and therefore it should be used with luate lung function compared to placebo. No ideoventricular rhythm, tachycardia, extrasys- precaution. Children. There are no specific reductions in exacerbations have been shown. toles, and skin eruptions. Patients with known recommendations in patients under 18 years. With regard to symptom related variables uncontrolled cardiovascular disease were ex- (dyspnea, quality of life), the minimum diffe- cluded form the clinical studies.3,4,11 Interactions1 rences considered clinically relevant were not The concomitant use of non-selective or selec- reached in the majority of the studies. Contraindications3 tive b-adrenergic blockers should be avoided, This combination has not shown any impro- Hypersensitivity to the drug or its excipients. unless there is sufficient reason to employ vement in either quality of life or a reduction in them. the use of rescue medication after 24 weeks. Warnings and precautions3 Concomitant use with other Neither has it shown a reduction in exacerba- · Precaution is necessary in patients with na- agents or long acting b2 adrenergic agents is tions nor has it been compared to other bron- rrow angle glaucoma not recommended. chodilators. · Precaution should also be taken in patients When comparing individual components with severe cardiovascular disorders, espe- EMA´s Risk Management Plan4 the clinical relevance of the results obtained cially heart arrhythms. The potential important risks identified in- in lung function were dubious, especially in · b2 agonists can produce hypokaliemia, which clude cardiovascular and cerebrovascular the case of umeclidinium alone. From a clini- can lead to cardiovascular adverse effects. disorders, paradoxical , narrow cal point of view the contribution afforded by It should not be administered concomitantly angle glaucoma, urinary retention and the use vilanterol (not authorized in monotherapy) is with other drugs producing hypokaliemia. in patients. questionable. Although the combination of in- · b2 agonist can also produce transitory hyper- The EMA considers that there is a need for dividual drugs in one device can be associated glycemia. Plasma levels of glucose should be research on cardiovascular and cerebrovascu- with better patient therapeutic compliance monitored in diabetes patients before star- lar events and pneumonia in comparison with than the individual drugs taken separately, this ting treatment. tiotropium through a post-approval observa- situation is not possible in this case because tional study. There is also information lacking vilanterol is not authorized as an individual Use in special situations3 on patients with liver failure and on long term treatment option. Pregnancy and lactation: There are no data safety. When compared to tiotropium the differen- available in pregnant women and its excretion ces in lung function were of uncertain clinical relevance and of no clinical relevance when evaluating symptom relief and quality of life. DAILY COST OF TREATMENT (E) The main concern on safety is the cardiovas- cular effects. More data is required to compare 24 mcg 0.75 its safety profile to that of tiotropium. 300 mcg 0.84 Given the available evidence, umeclidinium/ 100 mcg 1.19 vilanterol does not provide additional advanta- ges compared to other LABA/LAMA combina- 5 mcg 1.39 tions and there is a lack of adequately designed UmeclidiniUM 55 mcg 1.51 studies that support the possible efficacy in the AdidiriUM 644 mcg 1.59 reduction of exacerbations, an aspect already shown in studies on other existing alternatives. GlicopirroniUM 44 mcg 1.59 Therefore, given the poor evidence available on TiotropiUM 18 mcg 1.64 efficacy and safety, it is not clear whether this Formoterol/Bedometasone 24/400 mcg 1.72 drug has a role in the management of COPD. Vilanterol/ 22/92 mcg 1.72 Presentations Formoterol/ 640/18 mcg 1.73 Anoro® (GlaxoSmithKline ) 55/22 mcg 30 do- Salmeterol/Fluticasone 100/1000 mcg 2.49 ses (70.25 €) Indacaterol/Glicopirronium 85/43 mcg 2.87 References Umedidinium/Vilanterol 55/22 mcg 2.34 This information is based on the therapeutic positioning report of the AEMPS. 0.00 1.00 2.00 3.00

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