Moxifloxacina na Comunidade.

Apresentação em tema: "Moxifloxacina na Comunidade."— Transcrição da apresentação:

1 Moxifloxacina na Comunidade

2 DPOC na Pneumologia do HCM
consultas DPOC (2,6%) consultas DPOC (4%) Internamento %

3 Pneumonia na Pneumologia HCM
3ª causa de internamento com 13% Ambulatório - controle

4 MOXIFLOXACINA Quinolona 4ª geração
Interfere com as topoisomerases II e IV

5 Indicações Exacerbações agudas da bronquite crónica (EABC)⁄DPOC
Sinusite bacteriana aguda (SBA) Pneumonia adquirida na comunidade (PAC) excepto casos severos

6 Dosagem e administração
Prescrição Dosagem e administração Um comprimido de 400mg uma vez dia

7 Duração do tratamento EABC 5-10 dias PAC 10 dias SBA 7-10 dias

8 Efeitos colaterais The cumulative safety data for Avelox is well documented and can be summarised as follows: > Based on evidence from more than 12,800 in clinical trials and more than 92,000 in postmarketing studies. > The overall frequency of adverse drug reactions (ADRs) is similar to that of other commonly used antibiotics (amoxicillin, co-amoxiclav, clarithromycin, cefuroxime-axetil and levofloxacin). > Avelox is well tolerated in elderly patients and those with renal impairment. Apart from nausea and diarrhoea (which are common events for all antibiotics) all adverse reactions were observed at frequencies below 3%. Please refer to your country specific prescribing information for Avelox to learn detailed information on the adverse drug reactions of Avelox and the special warnings and precautions for use. Ball et al. Clin Ther 2004; 26:

9 Contra - Indicações Hipersensibilidade à moxifloxacina
Gravidez e lactação Crianças Doença do tendão Prolongamento da onda QT Disfunção hepática grave As with other quinolones Avelox has been shown to cause lesions in the cartilage of the weight bearing joints of immature animals. For this reason the use of Avelox in children and growing adolescents is contraindicated. The efficacy and safety of Avelox in children and adolescents have not been established. Tendon inflammation and rupture may occur with quinolone therapy, particularly in elderly patients, those concurrently taking corticosteroids and those who have had either a kidney, heart or lung transplant. At the first sign of pain or inflammation, patients should discontinue treatment with Avelox and rest the affected limb(s) and consult their doctor.

10 Prolongamento QT O prolongamento do intervalo QT pode causar arritmías graves incluindo “Torsades de pointes” Adverse drug reactions affecting the cardiovascular system are common for various drug classes. A number of cardiovascular events are related to the effect a drug has on the QT interval. The QT interval is one part of the electrical process that happens during a single heart beat and represents the time required for all ventricular depolarisation and repolarisation processes to occur. It is graphically represented by an electrocardiogram (ECG). The QT interval, the time taken to go from Q to T as recorded on the ECG, varies based on the heart rate. QTc is the QT interval corrected for heart rate. If QTc interval is longer than normal there is a risk of severe heart arrhythmias including so called ‘Torsades de pointes’ which is a form of ventricular tachycardia. This results in a series of rapid heartbeats which causes the heart to beat inefficiently. MacLean et al. The Pharmaceutical Journal 1999; 262:

11 Interacções Nenhuma com ranitidina, probenicide, suplementos de cálcio, morfina parenteral, teofilina e itraconazole. os antiácidos reduzem a absorção. Aumenta no plasma a digoxina e diminui a glibenclamida Aumenta a actividade da varfarina Sem interacção com alimentos ou álcool No interactions have occurred following concomitant administration of Avelox with: ranitidine, probenecid, oral contraceptives, calcium supplements, morphine administered parenterally, theophylline or itraconazole. As for all quinolones, antacids containing magnesium or aluminium and preparations containing metal ions such as iron reduce the absorption of Avelox. Therefore a gap of 6 hours should be left between administration of these agents and administration of Avelox. Concomitant administration with Avelox increases the peak plasma concentration of digoxin (no clinical relevance) and decreases the concentration of glibenclamide (without any impact on blood sugar levels). A large number of patients receiving antibiotics have experienced an increase in oral anticoagulant (e.g. warfarin) activity. Antibiotics that can have this effect include quinolones, macrolides, tetracyclines, cotrimoxazole and some cephalosporins. A precautionary measure would be to more frequently monitor the anticoagulant activity and, if necessary, the oral anticoagulant dosage should be adjusted as appropriate. Avelox has no interaction with food including dairy products and no interaction with alcohol.

12 Propriedades Farmacocinéticas
Pharmacokinetics is the study of how drugs are absorbed, distributed, metabolised and eliminated by the body. The table shows the key pharmacokinetic parameters of Avelox and their significance for treatment. Avelox tablets, EU Summary of Product Characteristics (SmPC), Oct 2008

13 Distribuição: Concentração no tecido pulmonar
When a drug is initially absorbed into the bloodstream from the gut it is carried to different organs and tissues throughout the body. Drugs, as a result of their chemical properties, have different affinities to different parts of the body. Consequently, depending on a drug’s affinity to different tissues it could concentrate in some areas more than others. For example, Avelox has a high affinity for lung tissue. This is a highly beneficial characteristic in its ability to eradicate RTIs. The graph shows the rapid penetration of Avelox into lung tissue after both an IV and oral dose with levels still detectable after 24 hours. These data confirm the long duration of action of Avelox at the site of infection allowing once daily administration. Breilh et al. J Chemother 2003; 15: 558–62

14 Eliminação Moxifloxacina (comprimidos) é quase completamente absorvido de forma rápida A semi vida é de 12 horas Moxifloxacina é excretado na urina e fezes Following oral administration Avelox 400mg tablets are rapidly and almost completely absorbed into the bloodstream. Half of the drug is cleared from the body in around 12 hours. The body eliminates Avelox in both the urine (19% is unchanged and 16.5% is eliminated as active metabolite) and faeces (25% is unchanged drug and 36% as inactive metabolite). When one route is compromised i.e. renal or liver impairment, elimination can still occur through the other route. This means that no dosage adjustments are required in patients with renal impairment or with mild/moderate hepatic impairment.

15 Farmacodinâmica: Actividade bactericida
CIM90 para o Moxifloxacina para os patogénios respiratórios mais comuns: S. pneumoniae – 0.25 mg/L H. influenzae – 0.03 mg/L M. catarrhalis – 0.12 mg/L C. pneumoniae – 0.12 mg/L M. pneumoniae – 0.12 mg/L L. pneumophila – 0.015–0.03 mg/L Concentração do Moxifloxacina nos tecidos respiratórios às 24 h após 400mg - PO excede as CIM90 para todos estes patogénios. The pharmacodynamics of a drug are defined as the effects of the drug on the body, or in the case of antibiotics, on the targeted organism or pathogen. In the case of Avelox, it is a very potent bactericidal antibiotic active against a wide variety of bacterial pathogens. In vitro studies have shown that the concentrations of Avelox in respiratory tissues exceed those required for bacterial eradication. Breilh et al. J Chemother 2003; 15: 558–62 Soman et al. J Antimicrob Chemother 1999; 44: 835–8 Jonas et al. J Antimicrob Chemother 2001; 47: 147–52

16 Moxifloxacina na EABC: principais estudos
MOSAIC e MOSAIC II EFEMAP IMPAC Moxifloxacina vs macrólidos, levofloxacina e co-amoxiclav

17 MOSAIC e MOSAIC II Wilson et al. Chest 2004; 125(3): 953-964
The baseline health status of the patient was assessed at enrolment and then the patient was randomised to treatment at the time of an exacerbation. Clinicians could choose one of the three standard first line antibiotics to be compared to Avelox, based on local pathogens and antibiotic resistance, but would actually not know whether their patient received Avelox or a comparator thereby keeping the study in a blinded fashion. This meant that each study centre was comparing Avelox against the most appropriate antibiotic in that locality. A total of 1,935 patients were enrolled in 103 centres, 733 patients were randomised, with 357 on Avelox and 376 on standard first line therapy. Patients were followed up in the short term i.e. contacted 5 to 7 days after randomisation with an examination 7 to 10 days after completing the treatment. Each patient was also followed up long term and was contacted on a monthly basis for a maximum of 9 months. The last visit occurred either at the time of the next exacerbation or at 9 months, whichever came first. Wilson et al. Chest 2004; 125(3):

18 MOSAIC taxas de cura clínica
The primary outcome measure was clinical success 7-10 days after the end of treatment which was defined as sufficient improvement in clinical signs and symptoms that no further antibiotics were needed for the current exacerbation. The investigators also measured: > Clinical cure which was defined as the return to the patients health status at enrolment (prior to having the exacerbation) > The number of patients requiring a further course of antibiotics for treatment of current exacerbation > The length of time to their next exacerbation Compared with standard first-line therapy Avelox showed clinical success after just 5 days > 5 days of Avelox was equivalent to 7 days of comparator therapy (87.2% vs 84.2%, 95%CI: -3.0 to 8.5) More patients returned to their pre-exacerbation health status - clinical cure - after Avelox treatment > 69.7% after 5 days of Avelox vs 62.1% after 7 days of comparator therapy (95% CI, 0.3– 15.6, statistically significant) Patients on standard first-line antibiotics were almost twice as likely to require a further course of antibiotics as those treated with Avelox: > 5 days of Avelox – 8.8% vs 7 days of comparator therapy – 14.8% (95% CI, 0.6 – 11.1, statistically significant)

19 Resultados a longo prazo do MOSAIC
Exacerbação seguinte Moxifloxacina: 133 dias vs comparador:118 dias (p=0.03) Os doentes estão melhores a longo prazo com a moxifloxacina em vez dos Ab comparadores. Many factors can influence the outcome of a study like MOSAIC over and above the antibiotics themselves. These can include the severity of the disease or use of concomitant medications. The investigators ran a further set of statistical analyses on the MOSAIC data to gain a better understanding of the factors that can affect patient outcome. Patients were likely to do better on the long term if they were treated with Avelox rather than standard comparator antibiotics. Wilson et al. Thorax 2006; 61:

20 EFEMAP Observacional, não randomizado, de 30 dias em 252 GP em Espanha
Doentes diagnosticados com COPD ou EABC receberam um dos seguintes regimes: • Moxifloxacina 400mg 1xd - 5 dias (n=575) • Amoxicilina/clavulanato 500mg/125mg 3xd - 10 dias (n=460) • Claritromicina 500mg 2xd - 10 dias (n=421)

21 Comparador - estudos: Macrólidos
A further study looking at the comparison of Avelox with macrolides in the treatment of AECB in general practice has been performed. This was a prospective, open label trial of nearly 2000 patients and dose of antibiotic and the duration of treatment was at the physicians discretion. Avelox showed superior overall treatment efficacy to the macrolides azithromycin, clarithromycin or roxithromycin (p<0.0001) There was also a significant difference in the mean time to improvement of 3.2 days with Avelox compared to 4.4 days with macrolides (p<0.0001). Schaberg et al. Clin Drug Invest 2006; 26: 733–44

22 Sumário Moxifloxacina e EABC
Moxifloxacina é excelente para o tratamento da EABC. Eficaz como tratamento empírico na comunidade e atrasa exacerbações futuras.

23 Moxifloxacina e PAC – principais estudos clínicos
Estudos de eficácia e segurança PMS Estudos comparativos penicilinas Penicilinas e/ou macrólidos

24 Estudo de post marketing surveillance (PMS) confirma eficácia na PAC
A PMS (post-marketing surveillance study), carried out in Germany, reviewed the data from 2188 patients treated with Avelox tablets for up to 10 days and reported 93.4% cured or improved. Avelox was well tolerated and the authors concluded that the product provided a rapid and comprehensive resolution of symptoms in a broad range of patients. Landen and Bauer. Clin drug Invest 2001; 21 (12):

25 Fase III resultados de eficácia
The pooled data from 6 Phase III multicentre studies were analysed retrospectively to determine the efficacy of Avelox on clinical cure rate and eradication of non-resistant and resistant strains of S. pneumoniae and is summarized below: Summary of the study design > Adult patients (n=131) with radiographically confirmed CAP with at least one baseline respiratory and/or one baseline blood isolate of S. pneumoniae > Primary endpoint: clinical success at test-of cure in patients with proven S. pneumoniae > Secondary endpoint: bacteriological responses based on repeat sputum and blood cultures > Susceptibility of S. pneumoniae isolates to 11 antimicrobial agents was assessed: Penicillin, cefuroxime, ceftriaxone, erythromycin, azithromycin, clarithromycin, clindamycin, moxifl oxacin, tetracycline, chloramphenicol, trimethoprim/ sulfamethoxazole > S. pneumoniae identified in pre-therapy cultures obtained from sputum, blood, bronchoscopy or open lung biopsy > All patients received oral or sequential IV / oral Avelox, 400 mg, for 7– 4 days The results showed a clinical cure rate of Avelox of over 94% with equal effectiveness against S. pneumoniae resistant to penicillin, macrolides and multi-drug resistant S. pneumoniae Fogarty et al. J Clin Pract 2005; 59:

26 Conclusão dos autores sobre a Fase III
Moxifloxacina é uma fluorquinolona apropriada para o tratamento de doentes com infecção por S. pneumoniae, incluindo estirpes resistentes aos antimicrobianos (não fluoroquinolonas) O número de antimicrobianos para o qual o isolado foi resistente não alterou a eficácia da Moxifloxacina Moxifloxacina pode ser considerado como opção empirica de 1ª linha para regiões com alta prevalência de PRSP e MDRSP

27 Estudos comparadores na PAC
Moxifloxacina e Amoxicilina Amoxicilina e/ou claritromicina amoxicilina-clavulanato mais roxitromicina claritromicina Petitpretz et al. Chest 2001; 119: Torres et al. Eur Resp J 2003; 21: 135–43 Portier et al. Eur J Microbiol Infect Dis 2005; 24: Grossman et al. ECCMID 2006, Poster P1706

28 Resultados dos estudos comparadores
Dose alta de amoxicilina Moxifloxacina foi tão eficaz como uma dose alta (1g tds) de amoxicilina em termos do sucesso clínico (91.5% vs 89.7%) e erradicação bacteriana (89.7% vs 82.4%). Avelox and amoxicillin A multinational, multicentre double-blind, randomised trial in 411 patients showed that: > Avelox was as effective as high dose (1g tds) amoxicillin in terms of clinical success (91.5% vs 89.7%) and bacterial eradication (89.7% vs 82.4%). From these data it was concluded that Avelox may, therefore, be an alternative for empiric CAP treatment especially in areas of high prevalence of MDRSP. Avelox and amoxicillin and/or clarithromycin A further large study recruiting 564 patients compared Avelox with either amoxicillin (1g tds) or clarithromycin (500mg bd) alone or in combination as first line therapy. This doubleblind, randomised trial was designed to mimic as far as possible the conditions relating to real world setting and physicians made a choice between the treatment regimens prior to randomisation. Results showed: > Cure rates at days (95.3% and 93.7%) showed that Avelox was as effective as standard therapy > Drug-related adverse event data (20% and 31%) showed that Avelox was better tolerated (p=0.004)

29 Moxifloxacina em estudos ABS
SPEED: tempo para erradicação bacteriana com Moxifloxacina SCALA estudo de eficácia e segurança do Moxifloxacina em ABS 7 e 10 dias de tratamento com Moxifloxacina vs comparadores Análise de dados de doentes tratados com Moxifloxacina e levofloxacina As described in Module 2 acute bacterial sinusitis is a very common disease seen frequently in general practice and is a major indication for the prescribing of antibiotics in the community. It is usually precipitated by a viral infection most commonly the “common cold” and some sufferers will go on to develop acute bacterial sinusitis. With the development of resistance to the penicillins and other classes by the causal pathogens in ABS this is an important area for the future growth of Avelox as an effective treatment option. Ariza et al. BMC Ear Nose Throat Disord 2006; 6: 8 Gehanno et al. Med Malad Infect 2002; 32: 494–507 Siegert et al. Respir Med 2000; 94: 337–44 Rakkar et al. Int J Clin Pract 2001; 55: 309–15 Keating et al. Curr Med Res Opin 2006; 22: 327–33

30 O estudo SPEED: Erradicação de patogénios
One of the most important trials is the SPEED study which looked for the first time at the time to bacterial eradication in ABS36. Other measures were clinical success rates and heath-related quality of life assessments. The results of bacterial eradication in 42 patients is shown above and showed that Avelox treatment after only two days resulted in the eradication of bacteria in over 80% of patients and 97.6% of patients after only 4 days. Avelox was also associated with high levels of clinical success (92.6%) and rapid improvement of symptoms as shown by the improvements in facial pain/ pressure in over 75% of patients after only 4 days treatment.

31 O estudo SCALA O estudo SCALA também confirmou a eficácia da Moxifloxacina em doentes nos quais a 1ª linha de tratamento falhou. Após 7-10 dias de tratamento com Moxifloxacina: Cura clínica foi observada em 93% dos doentes Erradicação bacteriana foi observada em 97%.

32 As Quinolonas As a relatively new class of antibiotics the quinolones offer a broader spectrum of activity and higher tissue penetration than the older types of drug. As described in Module 3, quinolones are DNA synthesis inhibitors which results in bacterial cell death. The earliest quinolones were developed in the 1960s. In 1987 Ciproxin (ciprofloxacin), developed and manufactured by Bayer, first came on the market and quickly became the gold standard quinolone for treatment of gram negative infections with a broad range of indications. Ciproxin was a very successful product and at its peak had worldwide sales of over $2 billion. Now Ciproxin is most commonly used in urinary tract infections by community physicians and there are generic alternatives available. Its activity against S. pneumoniae is suboptimal. With this in mind Bayer developed Avelox with an improved spectrum of activity against all of the key respiratory tract pathogens, including S. pneumoniae. The quinolones can be identified by the ending ‘floxacin’ and are classifi ed according to their generation.

33 109 milhões de doentes tratados em todo o mundo (Nov 2008)

34 Obrigada