U. Ugrasal. New Jersey Institute of Technology.
Tolerance was good 150 mg rulide overnight delivery, except for more cases of nausea (21 versus 14%) under elvitegravir order rulide 150 mg mastercard. In contrast generic rulide 150mg without a prescription, fewer cases of dizzi- ness (7 versus 24%) and dyslipidemia were observed generic 150 mg rulide with amex. The results were sustained over a period of 144 weeks (Clumeck 2014, Wohl 2014). There are, however, some problems with nephrotoxicity. Cobicistat inhibits renal tubular secretion of creatinine and increases serum creatinine levels, resulting in a decrease in estimated glomerular filtration rate (GFR) without a true decline in GFR. Thus, it may difficult to distinguish between these effects and the “true” renal toxicity of tenofovir. In the phase III studies, the GFR declined by 13–14 mL/min. There are detailed recommendations for renal monitoring during therapy with Stribild. In all patients, document estimated creatinine clearance (CrCl), urine glucose, and urine protein should be available at baseline. Stribild should not be initiated or discon- tinued when estimated CrCl is <70 or <50 mL/min, respectively. In 145, a large randomized double-blind Phase III trial on over 700 pre-treated patients with documented resistance showed similar effects with elvitegravir or raltegravir (Elion 2012). Consequently, Stribild can also be used in treatment-experienced patients without known resistance mutations to INSTIs. The switch from PIs or NNRTIs in patients with sustained virological suppression (and very limited resist- ance) is also possible, as shown by two large randomized trials (Arribas 2014, Pozniak 2014). It remains to be seen if Stribild is also potent in heavily pretreated patients. There seems to be at least two resistance pathways, located at the codons T66I or E92Q (Shimura 2008). In the case of Y143, a raltegravir resistance, efficacy seems to persist (Métifiot 2011). Resistance muta- tions of elvitegravir and raltegravir overlap to a great extent (Garrido 2012). No viro- logic response was observed in a small clinical study with patients who switched from elvitegravir to raltegravir (DeJesus 2007). Major interactions with elvitegravir are not expected, at least not with NRTIs, darunavir, tipranavir, fosamprenavir or etravirine. However, dose adjustments with lopinavir/r and atazanavir/r may be necessary. The dose of maraviroc must be halved (Ramanathan 2011). There are no clinically relevant interactions between boosted elvitegravir and H2-receptor antagonists or proton pump inhibitors. However, staggered antacid administration by 2 hours is recommended (Ramanathan 2013) In September 2014, elvitegravir as single agent was approved for use with a protease inhibitor coadministered with ritonavir plus other antiretrovirals. The approval was based upon results from the Phase III Study 145 (see above). Raltegravir (RAL, Isentress) is a strand transfer inhibitor and was the first integrase inhibitor on the market (Hazuda 2000). Raltegravir has a wide range of efficacy for R5 and X4 tropic viruses, and inhibits HIV-2 replication. During a 10-day monotherapy, viral load declined by two logs (Markowitz 2006). The encouraging results of an early Phase II study in extensively pre-treated patients (Grinsztejn 2007) were confirmed by two large Phase III studies which led to approval of raltegravir. In BENCHMRK-1 and -2, a total of 699 pretreated patients with triple- 6. Overview of antiretroviral agents 103 class resistance were randomized to raltegravir 400 mg BID or placebo, each combined with an optimized background therapy (Cooper 2008, Steigbigl 2008). After 16 weeks, 79% (versus 43%) of patients showed a viral load below 400 copies/ml. Even in patients initially without an active substance in their background therapy in geno- typic assays, the success rate reached 57% (versus 10%). The effects were sustained beyond 144 weeks (Eron 2010). Raltegravir has also been effective in treatment-naïve patients. The encouraging data from an early Phase II study (Markowitz 2009) were confirmed by a large Phase III study in which 563 patients received either raltegravir or efavirenz (Lennox 2009): at week 48, rates of patients achieving undetectable plasma viremia (<50 copies/ml) were 86% and 82%, respectively. Tolerability was better and the effects were main- tained over five years (Rockstroh 2013). In September 2009, raltegravir was approved for first-line therapy. In ACTG 5237, raltegravir was superior to the two boosted PIs atazanavir and darunavir (Landovitz 2014). Tolerability of raltegravir has so far been excellent. In BENCHMRK, raltegravir side effects were comparable to placebo. Apart from some anecdotal reports of rhab- domyolysis, hepatitis, rash and insomnia (Gray 2009, Santos 2009, Dori 2010, Tsukada 2010), frequently appearing side effects with raltegravir have not been seen. Raltegravir seems to be safe, including in those with hepatitis coinfections (Rockstroh 2012). In patients with renal impairment, no dosage adjustment is required. Expected autoimmune diseases observed in animal testing have so far not been clinically confirmed (Beck-Engeser 2010). There is limited data for pediatric or pregnant patients (Taylor 2011). Due to its excellent tolerability, raltegravir is currently being evaluated in the setting of nuke-sparing strategies (see below). The fact that viral load decreased more rapidly in the first weeks in patients taking raltegravir compared to those taking efavirenz led to some speculations about higher potency (Murray 2007). Several experimental studies looked at strategies aimed at achieving viral eradication with raltegravir intensification (see chapter on Eradication). However, some experts believe that the faster response on raltegravir- based regimens is not a matter of potency, but rather due to its unique effect of block- ing integration of the HIV genome (Siliciano 2009). There are at least two common resist- ance pathways, via mutations Q148K/R/H or N155H. Both mutations are localized within the catalytic core of the integrase (Grinsztejn 2007, Malet 2008). Resistance may occur quickly on a failing regimen (Grinsztejin 2007, Taiwo 2011). The resistance barrier of raltegravir seems not very high although it is higher than that for NNRTIs. A few days of monother- apy are not enough to select resistance mutations as is the case with nevirapine (Miller 2010). There is evidence for cross-resistance with elvitegravir (DeJesus 2007, Garrido 2012). Transmission of raltegravir-associated resistance mutations has been reported (Boyd 2011, Young 2011). This was shown by the randomized SWITCHMRK studies (Eron 2010) with more than 700 patients on a lopinavir/r-based ART with a viral load below 50 copies/ml for at least three months. Switching to ral- tegravir showed a better lipid profile, but did not demonstrate non-inferiority with respect to HIV RNA <50 copies/ml at week 24 versus remaining on lopinavir/r.
Based on findings from a more recent review of almotriptan trials cheap rulide 150 mg with mastercard, 70 however cheap rulide 150 mg without a prescription, similar rates of patients had sustained 24-hour pain-free outcomes with almotriptan 12 order rulide 150 mg with amex. One good-quality trial provided evidence that almotriptan 12 order rulide 150 mg amex. Both almotriptan and zolmitriptan tablets were encapsulated for blinding purposes. One fair-quality trial was designed primarily to compare patient preference for open almotriptan 12. Among the 255 of 327 patients in the 2-attack intention-to-treat population who recorded a preference for one triptan over another, half preferred almotriptan (n=128) and the other half preferred rizatriptan (n=127). This trial did not report quality-of-life or functional disability outcomes. Placebo-controlled trials: Almotriptan As 24-hour pain-free outcomes were not reported in head-to-head trials of almotriptan 12. We also included placebo-controlled trials of almotriptan 71 that analyzed consistent treatment across multiple headaches and early treatment of mild 72-74 migraine. Indirect comparison of almotriptan with the conventional tablet form of sumatriptan 100 mg for 24-hour pain-free. In their meta-analysis of 53 triptan trials, Ferrari and colleagues 75-77 included data from 3 abstracts of placebo-controlled trials of almotriptan 12. The actual mean value and 95% confidence interval was not provided for almotriptan but it was described as being higher than for the conventional tablet form of sumatriptan 100 mg. However, this comparison did not assess or adjust for potential clinical or methodological heterogeneity across trials. Therefore, we suggest that this finding be interpreted with caution. Triptans Page 34 of 80 Final Report Update 4 Drug Effectiveness Review Project Consistency. We found 1 fair-quality, placebo-controlled trial that examined the use of 71 almotriptan 12. The results of this trial demonstrated that a significantly greater number of patients achieved 2-hour pain-free outcomes in 3 of 3 headaches with almotriptan 12. The ‘AwM’ trial was designed to compare early and non-early intervention and involved 4 treatment groups. For the purposes of this review, our interest was in the 2 treatment groups in which patients were randomized to administer treatment with almotriptan or placebo when pain was still mild and within 1 hour of onset. Results from the other 2 treatment groups, in which patients were randomized to administer treatment with almotriptan or placebo when pain was moderate to ® severe, were reported separately and will not be discussed here. In the Axert Early Migraine Intervention Study, patients were allowed to treat pain of any intensity, as long as it was within 1 hour of onset, but outcomes for mild and moderate-to-severe headaches were reported separately. In both trials, almotriptan was superior to placebo in rates of 2-hour pain-free and 24-hour sustained pain-free. Rate of 2-hour pain-free in ‘AwM’ was 49% for almotriptan and 25% for placebo (odds ratio 2. Rate of 24-hour sustained pain-free was 46% for almotriptan and 16% for placebo in ‘AwM’, and in the ‘AEGIS’ trial was 25% and 16%, respectively (P=0. Based on our independent random-effects meta-analysis (Appendix D), these findings correspond to a pooled relative risk of 1. For 24-hour sustained pain-free rates, we calculated a pooled relative risk of 2. Functional disability and quality-of-life outcomes were also reported in a secondary publication of the 72 ‘AEGIS’ trial. At 2 hours, mean functional disability scores showed that significantly more patients functioned normally with almotriptan than placebo (54% compared with 38%; P=0. At 24 hours, scores in all 5 domains of the Migraine Quality-of-life Questionnaire were consistently better for almotriptan than placebo. Naratriptan Direct comparisons We included 2 head-to-head trials comparing naratriptan 2. No statistical analyses were performed on 24-hour outcome data, but naratriptan 2. The fair-quality trial did not report pain outcomes at 2 hours, but rates of 4-hour pain relief (76% compared with 84%) and 24-hour sustained relief (39% compared with 34%) were reported as similar for naratriptan 2. Neither trial reported on pain-free, workplace productivity, or quality of life. Both trials looked at treatment of only 1 headache per patient and thus did not provide data on consistency of response across multiple headaches. Triptans Page 35 of 80 Final Report Update 4 Drug Effectiveness Review Project Placebo-controlled trials: Naratriptan We found no placebo-controlled trials of naratriptan that reported quality of life, workplace productivity, or 2-hour or 24-hour pain-free outcomes. We also found no placebo-controlled trials that evaluated consistency of naratriptan across multiple headaches. Reformulated (rapid-release) oral sumatriptan Direct comparisons We found no head-to-head trial directly comparing reformulated (rapid-release) oral sumatriptan tablet with any other triptan. Placebo-controlled trials: Reformulated oral sumatriptan We included placebo-controlled trials of reformulated oral sumatriptan that looked at early 78, 79 treatment of migraine while pain is still mild. We also used data from placebo-controlled trials of reformulated sumatriptan 100 mg and the conventional tablet form of sumatriptan to explore indirect comparisons between the 2 formulations on 2-hour pain-free rates. The efficacy of reformulated sumatriptan 100 mg administered early in a migraine, while pain is mild, was demonstrated in a fair-quality trial of 432 adults who were 78, 79 instructed to administer treatment when pain was still mild and within 1 hour of onset. Rate of 2-hour pain-free was 66% for reformulated sumatriptan 100 mg and 20% for placebo (P<0. At 24 hours, rate of sustained pain-free also was significantly greater for reformulated sumatriptan 100 mg than placebo (40% compared with 10%; P<0. From these data, we calculated a relative risk of 3. Compared with placebo, rate of normal function was significantly greater for reformulated sumatriptan 100 mg at 45 minutes (29% compared with 18%; P<0. At 24 hours, significantly less time was lost on activities other than paid work for reformulated sumatriptan 100 mg (2. However, lost time in paid work was similar for reformulated sumatriptan 100 mg and placebo (2. Indirect comparison of reformulated with the conventional tablet form of sumatriptan. In the absence of head-to-head trials that directly compared reformulated and the conventional tablet form of sumatriptan, we explored indirect comparisons between formulations using data 80 from placebo-controlled trials. Data from placebo-controlled trials of reformulated sumatriptan 36, 37, 45, 81-85 and the conventional tablet form of sumatriptan were pooled, and combined relative risks and numbers needed to treat were generated for each triptan for 2-hour pain-free rates (Table 6). Estimates of relative risk were similar for the conventional tablet form of sumatriptan and reformulated sumatriptan and the large overlap of 95% confidence intervals did not suggest a clear advantage for either formulation over the other. However, the somewhat higher rate of 2- hour pain-free rates in the placebo group of the reformulated sumatriptan trial compared with those of the conventional tablet form of sumatriptan trials suggests the presence of at least some heterogeneity between the 2 sets of trials, likely in patient population or outcome assessment. Therefore, we caution against drawing firm conclusions about the comparison of reformulated and the conventional tablet form of sumatriptan until results from adjusted, quantitative, indirect comparisons, or head-to-head trials become available. Triptans Page 36 of 80 Final Report Update 4 Drug Effectiveness Review Project We also sought results on 24-hour sustained pain-free outcomes from placebo-controlled trials of reformulated and the conventional tablet form of sumatriptan, but insufficient data were available from trials of conventional sumatriptan. Pain-free at 2 hours in placebo-controlled trials: Pooled relative risk and number needed to treat for conventional and reformulated sumatriptan % sumatriptan % placebo Relative risk of 2 Heterogeneity: group pain- group pain- hr pain-free (95% Number Q (degrees of Sumatriptan free at 2 hr free at 2 hr confidence needed freedom), 100 mg (n/N) (n/N) interval) to treat P 7. But because the trials were poor quality, their findings will not be discussed here. We found no head-to-head trials comparing sumatriptan nasal spray with any other triptan. Placebo-controlled trials: Sumatriptan injection Indirect comparisons of subcutaneous sumatriptan to oral formulations of other triptans. Sumatriptan is the only triptan approved in the United States and Canada in an injectable form. Given the lack of fair-quality or good-quality head-to-head trials involving subcutaneous sumatriptan 6 mg, we examined findings of a good-quality systematic review that qualitatively evaluated indirect comparisons between subcutaneous sumatriptan 6 mg and other triptans on the basis of unadjusted estimates of relative risk calculated for each triptan using pooled data from 52 placebo-controlled trials. The main advantage of subcutaneous sumatriptan 6 mg over oral 86-89 90-96 triptans is that it could potentially provide earlier pain relief.
Among patients with prior exposure cheap rulide 150mg with visa, the benefit from fingolimod over interferon beta-1a ranged from 0 rulide 150 mg with visa. While the difference in annualized relapse rate between those with prior exposure and those without was not statistically significant purchase 150 mg rulide visa, the sample sizes may have been too small to identify the difference as significant order rulide 150 mg free shipping. Trial eligibility criteria required that participants had experienced at least 1 documented relapse during the previous year or at least 2 documented relapses during the previous 2 years. Although the trial used a double-dummy design, patients with prior experience with interferon may have been more likely to have guessed which treatment they were on, due to previously experiencing adverse effects associated with interferons but not fingolimod, such as injection site reactions. Because identifying the primary outcome of relapse requires subjective assessments by patients and neurologists, blinding of both parties is important to prevent potential bias (regardless of direction). The investigators attempted to maintain blinding of neurologists by having patients cover the injection site on days they were attending clinic for assessment. The success of blinding patients or neurologists was not evaluated, however. It is notable that the annualized relapse rates reported in all groups in this study (0. In the Drug Effectiveness Review Project report on Disease-modifying Drugs for Multiple Sclerosis, we found that annualized relapse rates ranged from 0. Explanations for this apparent difference may include the difference in duration of the trials, with the current study of fingolimod being only 12 months long, while the other studies were mostly 2 years in duration. However, it is also possible that the patients enrolled in this study were clinically distinct from those enrolled in the other studies, given that both diagnosis and treatment have changed over the past 10 years (the first head-to-head study of interferons was published in 2002). For example, review of the duration of multiple sclerosis at study enrollment revealed some variation, with a range of 4 to 6. This potential clinical heterogeneity in the patient populations reinforced the decision to not conduct an adjusted indirect comparison meta-analysis of these data. It is also noteworthy that interferon beta-1a was found to be the least effective interferon in our report, although it may have better tolerability ® than interferon beta-1b SC (Betaseron ). Confirmed disability progression (sustained worsening of disability score over 3 months) or time to progression, however, did not show a difference between the drugs or doses. Mean change from baseline on 2 scales measuring disability and function did show somewhat better results with both fingolimod doses compared with interferon, although these differences did not translate into differences in progression rates. Overall, there were no differences in the rate of discontinuation of the assigned treatment over 1 year (including both discontinuations for lack of efficacy and due to adverse events). The rate of progression reported in this trial ranged from 5. These rates were much lower than those found previously in the trials we reviewed of other disease-modifying drugs where rates of progression in beta interferon groups at 2 years ranged from 11. MS drugs addendum: fingolimod 16 of 32 Final Original Report Drug Effectiveness Review Project Table 3. Relapse rates with fingolimod compared with interferon beta-1a 30 mcg intramuscular weekly Fingolimod 0. Additional outcomes were presented in 2 posters submitted by the manufacturer. A post hoc analysis of the severity of relapse based on steroid use on an outpatient basis or hospitalization included all patients (N=1292). The rate of mild relapses (not requiring steroid use or hospitalization) was similar across the groups (3. The rate of outpatient steroid use was higher in the interferon group and when assessing the annualized relapse rate associated with patients requiring outpatient steroid use, fingolimod resulted in lower rates than interferon (Table 4). Similarly, the rate of hospitalization was lowest in the 0. Relapse outcomes based on steroid use or hospitalization Fingolimod 0. This analysis was based on a subset of the patients (64%) who had both baseline and 12 month assessments and a version of the PRIMUS scale in their language. The analysis of these results showed significantly greater worsening of total score in the interferon MS drugs addendum: fingolimod 17 of 32 Final Original Report Drug Effectiveness Review Project group when compared with either fingolimod group (mean change +0. However, the degree of change was not clinically meaningful in any group based on the definition of > 2 point improvement given in the study methods. An analysis comparing the percent of patients with improvement or worsening did not show differences between the drugs. Duration of effect Very little information was available on the duration of the beneficial effects with fingolimod beyond the 1-year trial. An extension study based on the study directly comparing these 2 drugs has been done (check posters), but has not been fully published to date. An extension study based on the placebo-controlled trial (below) has been reported and is discussed below. Indirect evidence Two fair-quality placebo-controlled trials, and 1 extension study of the smaller, have been 19, 22, 25 conducted. The first study was small (N=277), had MRI findings as the primary outcome, only lasted 6 months, and used doses higher than was ultimately approved by the US Food and Drug Administration (5 mg once daily and 1. While 89% of patients enrolled 14 had relapsing-remitting multiple sclerosis, 11% had secondary progressive disease. The study 19 also reported annualized relapse rates. The second study was larger (N=1272), lasted 2 years, used annualized relapse rates as the primary outcome measure, and used the lower doses of 0. This study enrolled only patients with relapsing-remitting 22 disease. As can be seen in Table 5 below, the annualized relapse rates in the placebo groups were different between the 2 studies. The study that included patients with secondary progressive disease had higher rates, as might be expected. Because the 2 studies are so different, we did not feel that pooling results from these studies would be clinically relevant. A US Food and Drug Administration analyses aggregated rates from all studies available at the time of the submission 14 and found a rate of 0. Results from placebo-controlled trials of fingolimod and interferon beta-1a and 1b (from the main Drug Effectiveness Review Project report on Disease-modifying Drugs for Multiple Sclerosis) are reported in Tables 5 and 6 below. Focusing on data relevant to the lower, approved dose of fingolimod, the annualized relapse rates in the placebo groups of the Kappos 2010 trial 22 of fingolimod 0. Similarly, the proportion of patients in the placebo groups with at least 1 relapse ranged from 44. Data on progression were more comparable, and patients having progressed at 2 years ranged from 20. The relative risk of having sustained progression of disability with fingolimod 0. MS drugs addendum: fingolimod 18 of 32 Final Original Report Drug Effectiveness Review Project Table 5. Clinical outcomes in placebo-controlled trials of fingolimod Kappos Kappos Kappos Kappos 2006 2006 2010 2010 Outcome measure 1. Clinical outcomes in placebo-controlled trials of interferons Outcome measure Interferon beta-1b Interferon beta- Interferon beta-1a SC ® ® ® (Interferon vs. Durability of effect The smaller placebo-controlled trial included an extension study where patients in the placebo 25 arms were re-randomized to 1. Because these doses were higher than those approved by the US Food and Drug Administration, and even the 1. There are now up to 4 years of data on this group of patients, however. At the end of the core study, 250 of the 277 enrolled patients joined the extension study. Based on a slide presentation submitted by the manufacturer, data after 4 21 years showed the rate in this group to remain at 63%. So, it appeared that there was an initial decrease over 2 years, but then stabilization for up to 4 years. It is noteworthy that the rate of relapse in the placebo group at the end of the core study was 66%, although it was only 6 months in duration. In contrast, the rate in the placebo group in the 2 year study was 46% at study end, indicating a potential benefit of drug over placebo after 2 and 4 years.
C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults M CL vsM CL +CS vsO N D vsO nd+CS vsG ranisetron N eedforR escueTherapy:29% vs16% vs6% vs3% vs22 generic 150 mg rulide with amex. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents R aynov 2000 R escuem edicationwasgiventoptswith ≥ 2episodesof vom iting orsevere SingleCenter chem o-inducednausea buy 150 mg rulide with amex. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity O ndansetroniv16m g Slaby 20m g iv G ranisetroniv3m g 38 150mg rulide amex. Antiemetics Page 87 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1 buy cheap rulide 150mg on-line. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics BE AM 200:67% Slaby BE AM 400:33% 2000 N R /N R /45 0/0/45 L ineagesof previoustherapy= 2%;range= 1%-5% SingleCenter Previouschem o-inducednausea:91% 5 Previouschem o-inducedvom itus(em esis):73% M eanheight= 169. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndansetronvsG ranisetronvsTropisetron N auseaand/orem esiscontrolfailure(for6and10days) Slaby 10days:80% vs46. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents BE AM conditioning regim enconsistsof 4cytotox ic drugs:D ay1= carm ustine300m g/m 2;D ay2-5:etoposide200or400m g/m 2/day;D ay2- O ndansetronvsG ranisetronvsTropisetron 5:cytosinearabinoside400m g/m 2/day;D ay6:m elphalan140m g/m 2. Thehighestincidenceof nausea SingleCenter Totalpatients: and/orem esiscontrolfailuresoccurredonD ay3(6pts)andonD ay7(7 5 Asthenia:4. Them ax im um incidenceof vom iting wasobservedfrom D ays7-10 (thepost-chem operiod). Studyprotocolam endedafterthestudyinitiationtoallow useof carboplatin atadoseof >200m g/m 2insteadof cisplatin. Chem o:cisplatin50-75m g/m 2adm inisteredasasingleiv O ndansetronvsG ranisetron infusionoveraperiodof ≤ 3hrs(co-adm inistrationof otherchem oagents Adverseevents wasperm ittedatthediscretionof theinvestigator,with theex ceptionof Spector F ever:3% vs1%,N S cyclophospham ideatadoseof ≥500m g/m 2,nitrogenm ustard, 1998 D iarrhea:3% vs0. N o M ulticenter M alaise/fatigue:3% vs4%,N S statisticallysignificantdifferencesex istedbetweentreatm entgroupsfor 5 Constipation:0. O f ptswhofailedtreatm ent,few didsowithinthe Anyadverseeventex perienced:24% vs28%,N S first3h;m ostfailedbetween6-24h afterthestartof chem o. N of ptswho Headache:7% vs12%,N S finishedappetitesurveyat24h:O nd= 136/184(73. N oex planationorreasongivenastowhydrop in num bersoccurredforthispartof thestudy. Antiemetics Page 90 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity O ndansetroniv+po16m g Stewart,A. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics M eansurfacearea= 1. Chem o:cyclophospham ide:1% 1995 Chem o:CM F :45% N R /N R /514 16/10/488 M ulticenter Chem o:AC com binations:3% 4 Chem o:E C com binations:33% O therCyclophospham idecom binations:12% Antiemetics Page 92 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndiv+povsO ndpovsG raniv E m esiscontrol:Acute(day1)R esults N o. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents Adverseeventsanalyseswereforall514patientsrandom iz ed;ITT analysis (488of 514)ex cluded26pts:16receivedincorrectantiem eticstreatm ent O ndiv+povsO ndpoonlyvsG ran priortochem oand10receivedantiem etic treatm entthatwasnotclearly Stewart,A. CM F = cyclophospham ide+m ethotrex ate+5-fluorouracil; 1995 Headache:7. F ornauseacontrol,theseverity of nauseawassignificantlyreducedwith both O ndregim enscom paredto theG rangroup (p= 0. Antiemetics Page 94 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity 8-m g IV bolusof dex am ethasonewas givenwith the StewartL. O ndansetroniv 8m g antiem etic onD ay1; 56 2000 D BR CT none G ranisetroniv 3m g and4m g dex powas N R /N R 43%m ale SingleCenter Crossover giventidondays2-4 N R 5 and/orm etoclopram ide 0or20m g orallyon days2-4. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics StewartL. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults O ndansetronvsG ranisetron Severityof nausea D ay1m eannauseascore(scale:0-3):0. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents Thestudywasdesignedwith arandom allocationusing aL atinsquare designinsetsof four. D ex = dex am ethasone;m eto= SingleCenter m etoclopram ide. E m esiscontrolinfowascollectedfor16pts(10wom en,6 5 m en)whohadreceived>1treatm enteach of O ndandG ran. Y alcn N odetailsonadverseeventsotherthan"theadverseevents,including Chem otreatm ent:Cyclophospham ide,adriam ycin,5-fluorouracil(CAF ); 1999 headaches,constipation,diarrhea,andinsom nia,wererareandm ildinall Cyclophospham ide,epirubicin,5-fluorouracil(CE F );Cyclophospham ide, SingleCenter groups"given. O necam efrom each 1998 AE data:"Therewerenosignificantsideeffectsineitherantiem etic antiem etic group,andtheirgenderswerenotspecified. Antiemetics Page 98 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity W alsh G ranisetroniv0. Antiemetics Page 99 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults G ranisetronvsO ndansetron Com pleteresponse:noem etic episodesandnone-to-m ildnausea D ay1:83% vs90%,N S; D ay2:70% vs84%,N S; D ay3:69% vs79%,N S; D ay4:54% vs56%,N S; D ay5:48% vs71%,N S; D ay6:50% vs46%,N S M ajorR esponse:1-2em etic episodesandnone-to-m oderatenausea;ornoem etic episodesandm oderatenausea D ay1:13% vs6%,N S D ay2:18% vs10%,N S D ay3:17% vs9%,N S D ay4:23% vs25%,N S W alsh D ay5:35% vs18%,N S 2004 D ay6:14% vs46%,N S M ulticenter M inorR esponse:3-5em etic episodesandanydegreeof nausea;or0-2em etic episodesandseverenausea 5 D ay6:36% vs8%,N S; D ay5:17% vs12%,N S D ay4:17% vs17%,N S D ay3:14% vs9%,N S D ay2:7% vs4%,N S D ay1:2% vs2%,N S F ailure:≥6em etic episodesandnaydegreeof nausea D ay1:2% vs2%,N S D ay2:5% vs2%,N S D ay3:0% vs2%,N S D ay4:6% vs3%,N S D ay5:0% vs0%,N S D ay6:0% vs0%,N S Antiemetics Page 101 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents O therm edsallowed:antihistam inesasprem edicationforblood transfusions;triaz olam ordiphenhydram ineforinsom nia. Chem o:Ptswho G ranisetronvsO ndansetron receivedbisulfan+cyclophospham ideasregim endidnotbeginstudydrug O verall untilcycloph. D iarrhea:9% vs12%,N S Thetotaldaysof studydrug dependedontypeof chem oadm inistered;so# Hypersensitivity:7% vs2%,N S of ptsreporting datavaried/day R escuem edication:prochlorperaz ine10m g Sedation:9% vs4%,N S W alsh ivevery6hrsasneeded(if theptshad3-5em etic episodesin24h orif the Trem ors:4% vs2%,N S 2004 ptrequestedit). Ptswererem ovedfrom studyif theyex perienceda O ther:9% vs12%,N S M ulticenter SouthwesternO ncologygroup (SW O G )grade3or4tox icity,otherthan Constipation:2% vs4%,N S 5 m yelotox icity,unlessitwasunrelatedtothestudym edication. R easons Hiccups:26% vs34%,N S 14/110ptswithdrawnafterrandom iz ation:5ptshadbaselinenauseaor Headache:2% vs10%,N S vom iting priortofirstdoseof studydrug ;5ptsreceivedm edicationwith Totalwithdrawals antiem etic activitynotperm ittedduring thestudyperiod;1ptreceived Studydrugscom bined:12. Antiemetics Page 102 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity Dolasetronvs O ndansetron D olasetroniv1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics Dolasetronvs O ndansetron previouschem otherapy:8% historyof heavyalcoholuse:16% H esketh CancerSite-L ung:55% 1996 N R /N R /609 51/N R /558 CancerSite-G astrointestinal:11% M ulticenter CancerSite-G ynecologic:10% 5 CancerSite-Head/N eck:11% CancerSite-O ther:14% Antiemetics Page 104 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults Dolasetronvs O ndansetron D olasetron1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents Dolasetronvs O ndansetron D olasetron1. L oraz epam was diarrhea:14% vs13% vs6%,N R notallowedduring 24h beforeorduring thestudyex ceptasarescue. Ptswerestratified H esketh chills:3% vs1% vs2%,N R into2groups:thosereceiving between70-91m g/m 2of cisplatin(m ean 1996 loosestools:1% vs2% vs2%,N R doseforthisgroup = 74. R escuem edicationwasgivenif apt fluidoverload:1% vs2% vs3%,N R requesteditorif aptex perienced>2em etic episodesduring the24h study AST increased:2% vs2% vs2%,N R period. Abstinencefrom narcotic analgesics,m alegender,andahistoryof headache:22% vs22% vs18%,N R heavyalcoholuse(presentorpastuseof ≥ 5drinks/day)werestatistically AL T increased:2% vs2% vs2%,N R significantpredictorsof ahigherCR rateacrossall3treatm entgroups. Antiemetics Page 106 of 492 Final Report Update 1 Drug Effectiveness Review Project Evidence Table 1. C h em oth erapy:H ead-to-h ead trials A uth or Y ear A ge Setting A llow oth er G ender H esketh rating Design Subpopulation Intervention m edication R un-in/W ash -out Eth nicity D olasetronpo25m g F auser D olasetronpo50m g 53. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Screened/ W ith drawn/ Setting Eligible/ L ostto fu/ H esketh rating Enrolled A nalyz ed O th erpopulationch aracteristics M eanheight= 165. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating R esults D olpo25vsD olpo50vsD olpo100vsD olpo200vsO ndpo32 Com pleteresponse(noem etic episodesandnoneedforrescuem edication): Allpts:45. C h em oth erapy:H ead-to-h ead trials A uth or Y ear Setting H esketh rating A dverse events C om m ents D oln25vsD ol50vsD ol100vsD ol200vsO nd AllAdverseE vents(AE s) Headache:11. Theone-postrandom iz ationwithdrawaloccurred N S whenaptreceivedthestudydrug butnotthechem odrugstheyhadbeen D iz z iness:0% vs2. Patientswerestratifiedbygenderandpriorchem o F auser D iarrhea:0% vs3.