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Medical Review(S) Team Leader Memorandum Application: NDA 21-821 Product: Tygacil (Tigecycline) for Injection Sponsor: Wyeth Pharmaceuticals, Inc. Date of Submission: December 15, 2004 Date of Memorandum: June 15, 2005 Tygacil (tigecycline) for injection, developed by Wyeth Pharmaceuticals, Inc., is the first glycylcycline class antibacterial drug. NDA 21-821 for tigecycline was submitted on December 15, 2004 seeking approval for complicated intra-abdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI). The indications list a variety of Gram-positive and Gram-negative bacteria, including MRSA, based on the results of the clinical trials. The application was granted a priority review as a new intravenous (IV) antibacterial drug, intended for the treatment of life-threatening disease, including MRSA infections, for which there are few treatment options. Glycylcyclines are structurally related to tetracycline antibiotics. Tigecycline is a derivative of minocycline, with a glycylamido- moiety attached to the 9 position of the tetracycline ring. The modification results in a compound that retains in vitro activity against bacteria that are tetracycline resistant. The in vitro data submitted by the sponsor show that tigecycline has broad spectrum activity. Tigecycline is active against several Gram-positive bacteria: Staphylococcus spp. including aureus, Streptococcus spp. including pyogenes, and Enterococcus spp. including faecalis. Tigecycline is also active against many Enterobacteriaceae: Escherichia coli, Klebsiella spp., Enterobacter aerogenes, Citrobacter freundii, and Acinetobacter spp. It is also active against other Gram-negative bacteria (Neisseria gonorrhoeae, Pasteurella multocida, Aeromonas hydrophila, and Stenotrophomonas maltophilia), with the notable exception of poor activity against Pseudomonas. Activity against anaerobes (Bacteroides spp., Clostridium spp.) was also reported. The clinical pharmacology of tigecycline shows that it is not orally absorbed, hence it is only available in a formulation for intravenous injection. Tigecycline has a long half-life (t½ = 44 hours after multiple doses). It also has a high steady-state volume of distribution, indicating extensive distribution to some tissues. Tigecycline is primarily excreted unchanged in the gall bladder, with a portion of the administered dose recovered unchanged in the urine. Tigecycline is not extensively metabolized, though there is some glucuronidation, N-acetylation, and conversion to an epimer (each no more than 10% of an administered dose). In initial studies, nausea was found to be a dose-limiting adverse effect. Based on the pharmacokinetic studies, a 100 mg IV loading dose followed by 50 mg IV twice daily was used in clinical trials. There were four pivotal phase 3 trials in the NDA submission for tigecycline, two for each indication. The results of these clinical trials are discussed by indication. Complicated Intra-abdominal Infections: Two phase 3, randomized, double-blind, multi-center trials compared tigecycline to imipenem/cilastatin in cIAI infections (Studies 301 and 306). The studies were independent trials, but a combined analysis of primary study results was pre-specified. Male or female patients (≥ 18 years of age) meeting the selection criteria were stratified by APACHE II score and randomized to study drug or comparator. Diagnoses included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis. Patients could receive tigecycline or comparator for 5-14 days, though >50% of patients received 6-8 days of study drug. The studies were designed to compare clinical outcome at the test-of-cure visit in the microbiological Intent-to-Treat (m-mITT) and microbiologically evaluable (ME) populations. Clinical outcome for the two trials are shown in the following table: Tigecycline a Imipenem/Cilastatin b c Studies Population n/N (%) n/N (%) 95% CI Study ME 199/247 (80.6) 210/255 (82.4) (-9.0, 5.4) 307A1-301 m-mITT 227/309 (73.5) 244/312 (78.2) (-11.8, 2.3) Study ME 242/265 (91.3) 232/258 (89.9) (-4.0, 6.8) 307A1-306 m-mITT 279/322 (86.6) 270/319 (84.6) (-3.7, 7.7) a 100 mg initially, followed by 50 mg every 12 hours b Imipenem/Cilastatin (500 mg every 6 hours) c 95% Confidence Intervals for the difference in clinical cure rates The clinical outcomes by pathogen in the ME population are shown in the table below: Tigecycline Imipenem/Cilastatin Pathogen n/N (%) n/N (%) Citrobacter freundii 12/16 (75.0) 3/4 (75.0) Enterobacter cloacae 14/16 (87.5) 16/17 (94.1) Escherichia coli 281/329 (85.4) 298/343 (86.9) Klebsiella oxytoca 19/20 (95.0) 18/20 (90.0) Klebsiella pneumoniae 46/52 (88.5) 53/60 (88.3) Enterococcus faecalis (vancomycin- susceptible only) 25/33 (75.8) 35/47 (74.5) Methicillin-susceptible Staphylococcus aureus (MSSA) 26/29 (89.7) 22/24 (91.7) Streptococcus anginosus grp.b 102/120 (85.0) 61/81 (75.3) Bacteroides fragilis 67/87 (77.0) 60/74 (81.1) Bacteroides thetaiotaomicron 36/41 (87.8) 31/36 (86.1) Bacteroides uniformis 12/17 (70.6) 14/17 (82.4) Bacteroides vulgatus 14/16 (87.5) 5/7 (71.4) Clostridium perfringens 19/20 (95.0) 20/22 (90.9) Peptostreptococcus micros 14/18 (77.8) 9/12 (75.0) The two studies demonstrated non-inferiority of tigecycline to the approved comparator with successful clinical outcomes in patients with a variety of intra-abdominal pathogens. Complicated Skin and Skin Structure Infections: Two phase 3, randomized, double- blind, multi-center trials compared tigecycline to the combination of vancomycin and aztreonam in cSSSI infections (Studies 300 and 305). The studies were independent trials, but a combined analysis of primary study results was pre-specified. Male or female patients (≥ 18 years of age) meeting the selection criteria were randomized to study drug or comparator. The main diagnoses were deep soft tissue infections or major abscesses. Diabetes and peripheral vascular disease were underlying conditions in approximately 20% and 7% of patients, respectively. Patients could receive tigecycline or comparator for up to 14 days. The studies were designed to compare clinical outcome at the test-of- cure visit in the clinical modified Intent-to-Treat (c-mITT) and clinically evaluable (CE) populations. Clinical outcome for the two trials are shown in the following table: Tigecycline a Vancomycin/Aztreonam b c Studies Population n/N (%) n/N (%) 95% CI Study CE 165/199 (82.9) 163/198 (82.3) (-7.4, 8.6) 3074A1-300 c-mITT 209/277 (75.5) 200/260 (76.9) (-9.0, 6.1) Study CE 200/223 (89.7) 201/213 (94.4) (-10.2, 0.8) 3074A1-305 c-mITT 220/261 (84.3) 225/259 (86.9) (-9.0, 3.8) a 100 mg initially, followed by 50 mg every 12 hours b Vancomycin (1 g IV every 12 hours)/Aztreonam (2 g IV every 12 hours) c 95% Confidence Intervals for the difference in clinical cure rates The clinical outcomes by pathogen in the ME population are shown in the table below: Vancomycin/ TYGACIL Aztreonam Pathogen n/N (%) n/N (%) Escherichia coli 27/32 (84.4) 26/30 (86.7) Enterococcus faecalis (vancomycin-susceptible only) 13/17 (76.5) 24/29 (82.8) Methicillin-susceptible Staphylococcus aureus (MSSA) 125/139 (89.9) 118/126 (93.7) Methicillin-resistant Staphylococcus aureus (MRSA) 29/37 (78.4) 26/34 (76.5) Streptococcus agalactiae 8/8 (100) 11/13 (84.6) Streptococcus anginosus grp. a 16/20 (80.0) 9/10 (90.0) Streptococcus pyogenes 31/33 (93.9) 24/27 (88.9) Bacteroides fragilis 6/8 (75.0) 4/5 (80.0) a Includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus The trials demonstrated non-inferiority of tigecycline to the combination of vancomycin and aztreonam in the treatment of cSSSI patients. Similar clinical outcomes were seen for patients with documented baseline pathogens treated with tigecycline and comparator. Of note, similar outcomes were reported for patients with cSSSI due to MRSA treated with tigecycline or vancomycin. Safety data were collected from 1,415 tigecycline-treated patients and 1382 comparator- treated patients in phase 3 clinical trials. The most common adverse reactions were nausea, vomiting, and diarrhea. The following table shows the incidence of nausea and vomiting as treatment-emergent adverse events in all four comparative trials, and also separated by indication. Of note, nausea and vomiting are reported at a much higher rate in tigecycline-treated patients than vancomycin/aztreonam-treated patients in the cSSSI trials. This difference between treatments is much smaller in the cIAI trials, mostly due to an increase in the rate of nausea and vomiting among comparator-treated patients. Nausea and vomiting are treatment-related adverse events occurring in tigecycline-treated patients. Tigecycline Comparator n/N* % n/N* % Nausea All Pivotal Trials 460/1396 33.0 274/1391 19.7 cSSSI Trials 207/570 36.3 54/559 9.7 cIAI Trials 253/826 30.6 220/832 26.4 Vomiting All Pivotal Trials 307/1396 22.0 185/1391 13.3 cSSSI Trials 117/570 20.5 25/559 4.5 cIAI Trials 190/826 23.0 160/832 19.2 * This analysis only includes patients participating in the four studies (300, 301, 305, and 306) In the serious adverse events associated with tigecycline use, it was noted that there were more deaths in the tigecycline-treated patients, 32/1383 (2.3%), than in comparator- treated patients 22/1375 (1.6%). This was not a statistically significant difference, and deaths in an even higher percentage of patients hospitalized due to these types of infections would be understandable. However, an intensive review of the deaths occurring in these trials was conducted, to try to understand whether specific drug-related factors (whether safety issues or lack of efficacy) may have contributed to this difference. No specific safety or efficacy findings could be found to account for this difference.
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