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Cumulative Incidence Rate, %: Rifabutin (n= 223)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 83.4 7.2 8.1 1.3
12 60.1 15.2 16.1 8.5
18 40.8 21.5 24.2 13.5
Cumulative Incidence Rate, %: Azithromycin (n= 223)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 85.2 3.6 5.8 5.4
12 65.5 7.6 16.1 10.8
18 45.3 12.1 23.8 18.8
Cumulative Incidence Rate, %: Azithromycin/ Rifabutin Combination (n= 218)
Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up
6 89.4 1.8 5.5 3.2
12 71.6 2.8 15.1 10.6
18 49.1 6.4 29.4 15.1 Comparing the cumulative one year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin- azithromycin) in the one year rates (7.6%) is statistically significant (p= 0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/ rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin- azithromycin/ rifabutin) in the cumulative one year incidence rates (12.5%) is statistically significant (p< 0.001) with an adjusted 95% confidence interval of (6.6%, 18.4%). The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference.
In Study 174, sensitivity testing 5 was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin or the combination. The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between study arms. As the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical relevance of these in vitro MICs as an indicator of susceptibility or resistance is not known. Text Continues Below
Clinically Significant Disseminated MAC Disease In association with the decreased incidence of bacteremia, patients in the groups randomized to
either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss and anemia.
Discontinuations From Therapy For Drug-Related Side Effects In Study 155, discontinuations for drug-related toxicity occurred in 8.2% of subjects treated with azithromycin and 2.3% of those given placebo (p= 0.121). In Study 174, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p= 0.026) or rifabutin alone (15.9%; p= 0.209).
Safety As these patients with advanced HIV disease were taking multiple concomitant medications and experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse events to study medication. Overall, the nature of side effects seen on the weekly dosage regimen of azithromycin over a period of approximately one year in patients with advanced HIV disease was similar to that previously reported for shorter course therapies. INCIDENCE OF ONE OR MORE TREATMENT RELATED* ADVERSE EVENTS** IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED
MAC OVER APPROXIMATELY 1 YEAR
Study 155 Study 174
Placebo (N= 91)
Azithromycin 1200 mg
weekly (N= 89)
Azithromycin 1200 mg
weekly (N= 233)
Rifabutin 300 mg
daily (N= 236)
Azithromycin + Rifabutin (N= 224) Mean Duration of Therapy (days) 303.8 402.9 315 296.1 344.4
Discontinuation of Therapy 2.3 8.2 13.5 15.9 22.7 Autonomic Nervous System
Mouth Dry 0 0 0 3.0 2.7 Central Nervous System
Dizziness 0 1.1 3.9 1.7 0.4 Headache 0 0 3.0 5.5 4.5
Gastrointestinal Diarrhea 15.4 52.8 50.2 19.1 50.9 Loose Stools 6.6 19.1 12.9 3.0 9.4 Abdominal Pain 6.6 27 32.2 12.3 31.7
Dyspepsia 1.1 9 4.7 1.7 1.8 Flatulence 4.4 9 10.7 5.1 5.8
Nausea 11 32.6 27.0 16.5 28.1 Vomiting 1.1 6.7 9.0 3.8 5.8
General Fever 1.1 0 2.1 4.2 4.9 Fatigue 0 2.2 3.9 2.1 3.1 Malaise 0 1.1 0.4 0 2.2
Musculoskeletal Arthralgia 0 0 3.0 4.2 7.1 Psychiatric Anorexia 1.1 0 2.1 2.1 3.1
Skin & Appendages Pruritus 3.3 0 3.9 3.4 7.6
Rash 3.2 3.4 8.1 9.4 11.1 Skin discoloration 0 0 0 2.1 2.2
Special Senses Tinnitus 4.4 3.4 0.9 1.3 0.9 Hearing Decreased 2.2 1.1 0.9 0.4 0 Uveitis 0 0 0.4 1.3 1.8
Taste Perversion 0 0 1.3 2.5 1.3
* Includes those events considered possibly or probably related to study drug ** >2% adverse event rates for any group (except uveitis). Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/ 233 (3.8%) of patients. Changes in Laboratory Values In these immunocompromised patients with advanced HIV infection, it was necessary to assess laboratory abnormalities developing on study with additional criteria if baseline values were outside the relevant normal range. Prophylaxis Against Disseminated MAC Abnormal Laboratory Values*
Placebo
Azithromycin 1200 mg
weekly
Rifabutin 300 mg
daily Azithromycin & Rifabutin Hemoglobin <8 g/ dl 1/ 51 2% 4/ 170 2% 4/ 114 4% 8/ 107 8%
Platelet Count <50 × 10 3 /mm 3 1/ 71 1% 4/ 260 2% 2/ 182 1% 6/ 181 3% WBC Count <1 × 10 3 /mm 3 0/ 8 0% 2/ 70 3% 2/ 47 4% 0/ 43 0%
Neutrophils <500/ mm 3 0/ 26 0% 4/ 106 4% 3/ 82 4% 2/ 78 3% SGOT >5 × ULN a 1/ 41 2% 8/ 158 5% 3/ 121 3% 6/ 114 5%
SGPT >5 × ULN 0/ 49 0% 8/ 166 5% 3/ 130 2% 5/ 117 4% Alk Phos >5 × ULN 1/ 80 1% 4/ 247 2% 2/ 172 1% 3/ 164 2% a =Upper Limit of Normal
*excludes subjects outside of the relevant normal range at baseline Treatment of Disseminated MAC Disease One randomized, double blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV infected patients with disseminated MAC received either azithromycin 250 mg qd (N= 65), azithromycin 600 mg qd (N= 91) or clarithromycin 500 mg bid (N= 90), each administered with ethambutol 15 mg/ kg qd, for 24 weeks. Patients were
cultured and clinically assessed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to any open label therapy at the discretion of the investigator and followed every 3 months through the last follow up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during study treatment or post-treatment were obtained whenever possible. The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC. The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg bid. Efficacy results for the azithromycin 600 mg qd and clarithromycin 500 mg bid treatment regimens are described in the following table:
Response to therapy of patients taking ethambutol and either azithromycin 600 mg qd or clarithromycin 500 mg bid Azithromycin 600 mg qd Clarithromycin 500 mg bid ** 95.1% CI on difference
Patients with positive culture at baseline 68 57
Week 24 Two consecutive negative blood cultures* 31/ 68 (46%) 32/ 57 (56%) [-28, 7] Mortality 16/ 68 (24%) 15/ 57 (26%) [-18, 13]
* Primary endpoint ** [95% confidence interval] on difference in rates (azithromycin-clarithromycin) The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg qd group than in the clarithromycin 500 mg bid group.
Sterilization by Baseline Colony Count Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC
cfu/ mL increased. Azithromycin 600 mg (N= 68) Clarithromycin 500 mg bid (N= 57)
Groups Stratified by MAC Colony Counts at
Baseline
No. (%) Subjects in Stratified Group Sterile at
Week 24
No. (%) Subjects in Stratified Group Sterile at
Week 24 10 cfu/ mL 10/ 15 (66.7%) 12/ 17 (70.6%) 11-100 cfu/ mL 13/ 28 (46.4%) 13/ 19 (68.4%) 101-1,000 cfu/ mL 7/ 19 (36.8%) 5/ 13 (38.5%)
1,001-10,000 cfu/ mL 1/ 5 (20.0%) 1/ 5 (20%) >10,000 cfu/ mL 0/ 1 (0.0%) 1/ 3 (33.3%) Susceptibility Pattern of MAC Isolates Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from <4 to >256 µ g/ mL and clarithromycin MICs ranged from <1 to >32 µ g/ mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32 fold higher than clarithromycin MIC values. During study treatment and post-treatment follow up for up to 3.7 years (median: 9 months) in study 189, a total of 6/ 68 (9%) and 6/ 57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg bid, respectively, developed MAC blood culture isolates that had a sharp increase in MIC values. All twelve MAC isolates had azithromycin MIC's 256 µ g/ mL and clarithromycin MIC's >32 µ g/ mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide. ANIMAL TOXICOLOGY Phospholipidosis (intracellular phospholipid binding) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e. g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs administered doses which, based on pharmacokinetics, are as low as 2 times greater than the recommended adult human dose and in rats at doses comparable to the recommended adult human dose. This effect has been reversible after cessation of azithromycin treatment. The significance of these findings for humans is unknown. REFERENCES: 1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically- Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December 1993. 2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests- Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993. 3. Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium chemoprophylaxis. American J Medicine 1997; 102( 5C): 37-49. 4. Meier A, Kirshner P, Springer B, et al. Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994; 38: 381-384. 5. Methodology per Inderlied CB, et al. Determination of In Vitro Susceptibility of Mycobacterium avium Complex Isolates to Antimicrobial Agents by Various Methods. Antimicrob Agents Chemother 1987; 31: 1697-1702.
Rx only Licensed from Pliva 2003 PFIZER INC Distributed by:
69-4763-00-9 Revised October 2003
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