H.6.G.2 Non-MAC Studies

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1 Page 63 H.6.G.2 Non-MAC Studies H.6.G.2.A Non-MAC Studies at the 600 mg dose A 600 mg dose of azithromycin was given in two non-mac studies (354/354A and 167). Please note: Study 354/354A enrolled a mixture of subjects, both MAC and non-mac. Subjects being treated for MAC in Study 354/354A received a 600 mg daily dose of azithromycin, while those with toxoplasmosis received a 1200 mg dose followed by a 600 mg maintenance dose. This section reports concomitant medication use for all subjects. Use of concomitant medication(s) was reported for 572 (90.1%) of the 635 subjects in this study. The most frequently used class of drug was antibacterial drugs (515 subjects, 81.1%), followed by antiviral drugs (463 subjects, 72.9%), antifungal drugs (419 subjects, 66.0%); antiprotozoal drugs (287 subjects, 45.2%) and analgesics (234 subjects, 36.9%) (354/354A-Appendix I, Table 2). Use of concomitant medication(s) was reported for 78 of the 130 subjects (60.0%) in Study 167. The most frequently used classes of drug was antiviral drugs (65 subjects, 50.0%), antibacterial drugs (62 subjects, 47.7%), antifungal drugs (55 subjects, 42.3%) and analgesics (48 subjects, 36.9%) (167-Appendix I, Table 2). H.6.G.2.B Non-MAC studies at Doses other than 600 mg Concomitant medications were used by >90% of the subjects in each of the 6 studies of azithromycin at doses other than 600 mg in the treatment of non-mac infection. The most commonly used concomitant medications were various classes of anti-infective drugs. Oral Dosing: Study 133 AIDS patients with toxoplasmic encephalitis received an 1800 mg loading dose given as two 900 mg doses 12 hours apart on day 1 followed by a 1200 mg single daily dose to complete 6 weeks of therapy. Those subjects weighing less than 50 kg were given a 1200 mg loading dose followed by a 600 mg daily dose to complete six weeks of treatment. Subjects that satisfactorily completed 6 weeks of primary therapy were eligible for suppressive therapy (900 mg daily) for as long as deemed clinically appropriate. Ninety-three (93) of the 95 subjects who received oral azithromycin received at least one concomitant medication. The most frequently used concomitant medication was antiviral drugs (74 of 95 subjects, or 77.9%) (133-Appendix I, Table 2). Study 143 Subjects with AIDS and intestinal cryptosporidiosis were randomized to receive either 900 mg of azithromycin or placebo for 21 days. Those subjects randomized to azithromycin in the first phase then received 300 mg daily for an additional 21 days (second phase). Those subjects initially randomized to placebo for the first 21 days then received 900 mg of azithromycin for the next 21 days. After two weeks of double-blind therapy, those subjects who demonstrated a worsening of their cryptosporidiosis could receive 1200 mg azithromycin as salvage treatment for up to 3 weeks. Following satisfactory completion of full-dose therapy (double-blind or open-label), subjects could continue receiving azithromycin as maintenance therapy in Study 167S. The data provided below are for subjects in Study

2 Page 64 Use of at least one concomitant medication was reported by all of the 40 subjects in the 900 mg group, all of the 41 subjects in the placebo group, and all of the 70 subjects who received maintenance treatment with azithromycin. The most frequently used concomitant medication was antiviral therapy (35, or 87.5% of the subjects in the azithromycin 900 mg group; 33 or 80.5% of the subjects in the placebo group; and 57, or 81.4%, of the subjects in the azithromycin maintenance therapy group) (143-Appendix I, Table 2). Study 167S For acute therapy in this study, adult subjects received a loading dose (two 1200 mg doses 12 hours apart) on day 1 followed by a single oral daily dose of 1200 mg for the next 27 days. Pediatric subjects received two 20 mg/kg oral doses 12 hours apart on day 1 followed by daily oral doses of 20 mg/kg for the next 27 days. For extended therapy, adult subjects received 600 mg/day and pediatric subjects received 10 mg/kg/day, not to exceed 600 mg. Subjects who relapsed during suppressive therapy could be placed on a second 28-day course of acute therapy. Following satisfactory completion of full-dose therapy (double-blind or open-label) in Study 143, subjects could continue receiving azithromycin as maintenance therapy in Study 167S. Both of the pediatric subjects and 59 of the 94 (62.8%) of the adult subjects who received oral azithromycin only in Study 167S received at least one concomitant medication. The most frequently used classes of drug were antibacterial drugs (47 adult subjects and 2 pediatric subjects, for a total of 49/96 subjects, or 51.0%), antiviral drugs (45 adult subjects and 1 pediatric subject, for a total of 46/96 subjects, or 47.9%), and antifungal drugs (40 adult subjects and 0 pediatric subjects, for a total of 40/96 subjects, or 41.7%) (167S- Appendix I, Table 2). Three (3) subjects in this study were included as other treated subjects ; 2 of these (66.7%) were known to have received at least one concomitant medication (167S- Appendix I, Table 2). Study 330 AIDS patients with toxoplasmic encephalitis received azithromycin 1000 mg once daily on day 1 followed by 500 mg once daily for 27 days. Pyrimethamine and folinic acid were protocol-specified concomitant therapy in this protocol. All of the 18 subjects in this study received at least one concomitant medication. The most commonly used class of drugs was drugs used to treat megaloblastic anemias (17 subjects, 94.4%), and the next most common class was antimalarials (12 subjects, or 66.7%) (330-Appendix I, Table 5). Study 338 AIDS patients with cryptosporidiosis received azithromycin 500 mg bid on day 1 followed by 500 mg daily for 13 or 20 days depending on response. Fourteen of the 15 subjects (93.3%) received at least one concomitant medication; the most commonly used classes of drugs were polyene antifungals and triazole antifungals (12 subjects each, 80.0%), followed closely by analgesics (11 subjects, 73.3%) (338-Table 1A and Appendix I, Table 5). Study 356 There were two parts (A and B) to this study treating cryptosporidial diarrhea in HIV infected subjects. In Part A azithromycin was given at 900 mg bid on day 1 and then 1200 mg once a day for 20 days. One group was randomized to receive azithromycin followed by placebo and a second group were randomized to receive placebo followed by -395-

3 azithromycin. In Part B azithromycin was given as 600 mg once a day for 24 weeks. Twelve subjects received 600 mg azithromycin for up to 20 weeks in Part B. Page 65 All of the 16 subjects who received azithromycin and 16 of the 19 subjects (84.2%) who received placebo received at least one concomitant medication; the most frequently reported were sulfonamides and trimethoprim, which were used by 14 subjects in the azithromycin group (87.5%) and 14 subjects in the placebo group (73.7%), and antiviral drugs, which were used by 14 of the subjects (87.5%) who received azithromycin and 13 of the subjects (68.4%) who received placebo (356-Table 1 and Appendix I, Table 5A). All of the 12 of the subjects who received azithromycin treatment in Part B (after the end of the double-blind period) received concomitant medications (356-Table 1 and Appendix I, Table 5B). Intravenous Dosing Study 133 AIDS patients with toxoplasmic encephalitis could receive intravenous azithromycin for up to 14 days. Adults could receive up to 2.0 grams of azithromycin per day, with the corresponding dose in children being 20 mg/kg daily. Those subjects who demonstrated a favorable clinical response were eligible to receive an additional 14 days of intravenous therapy. Those subjects could then receive oral azithromycin (1200 mg daily) over a period of 2 weeks for a total of 6 weeks of therapy. Subjects that satisfactorily completed 6 weeks of primary therapy were eligible for suppressive therapy (900 mg daily) for as long as deemed clinically appropriate. Three (3) of the four subjects (75.0%) who received intravenous azithromycin received at least one concomitant medication; the most frequently used were used by three subjects each: antibacterial drugs; antiepileptics; antiprotozoal drugs; drugs used in anemias; and hypnotics, sedatives and anxiolytics (133-Appendix I, Table 2). Study 167S Hospitalized subjects could receive intravenous azithromycin for up to 14 days as initial therapy if they had severe diarrhea as a result of severe cryptosporidial enteritis or had started on oral acute therapy and worsened or failed to respond. The adult dose was 1.0 gm daily; however, this dose could be increased to 2.0 gm per day for up to 14 more days. Prior to July 22, 1993, subjects with severe diarrhea could receive intravenous azithromycin for up to 10 days of acute treatment at a dose of 500 mg bid on day 1, followed by 500 mg daily for 9 days. The dose for children was 20 mg/kg as a single daily dose with no single intravenous dose to exceed 1.0 gm. Subjects having a favorable response to intravenous therapy could switch to oral azithromycin (1200 mg/day) to complete 28 days of acute therapy. One hundred four (104) subjects (18 pediatric and 86 adult) received intravenous azithromycin with or without the addition of oral therapy. Fifty-eight (58) of the 86 (67.4%) of the adult subjects and 14 of the 18 (77.8%) of the pediatric subjects who received intravenous (with or without oral) azithromycin in Study 167S received at least one concomitant medication. The most frequently used types of drugs were antibacterial drugs (43 adult and 12 pediatric subjects, for a total of 55/104 subjects, or 52.9%), antifungal drugs (41 adult and 11 pediatric subjects, for a total of 52/104 subjects, or 50.0%), and antiviral drugs (40 adult and 9 pediatric subjects, for a total of 49/104 subjects, or 47.1%) (167S-Appendix I, Table 2)

4 Page 66 H.6.G.3 Miscellaneous and Terminated Studies Information collected about the concomitant medications used by the small number of subjects enrolled in the miscellaneous and terminated studies (N<10 per study), if applicable, can be found in the individual study reports. H.6.G.4 Phase I Studies The protocols for all Phase I studies strictly limited the use of concomitant medications immediately prior to, and during, the study. The only type of concomitant medication that was frequently reported during the treatment phase of these studies was contraceptives (classified as oral contraceptives or sex hormones). These were used to fulfil the protocol requirement of contraception for female subjects of childbearing potential. H.6.G.5 Conclusions Concomitant medication use was high in all studies, and highest (100%) in the pivotal and primary supportive studies, where enrollment was limited to AIDS patients. In most studies, antibacterials were the most frequently used class of concomitant medication. Antiviral drugs were also very frequently used, but different studies had different rates of antiviral drug use, reflecting the differences in study population. Other frequently-used categories were antifungal and antiprotozoal drugs. H.6.H CLINICAL LABORATORY ABNORMALITIES The Premature Discontinuation section (Section H.6.C) gives a detailed account of the subjects who discontinued due to laboratory abnormalities from the studies of azithromycin in the treatment of MAC and other opportunistic infections included in this submission. Among the subjects who received azithromycin in the three pivotal and primary supportive studies, 7 discontinued due to laboratory abnormalities (Section H.6.C.1.A). Previous clinical experience with azithromycin at doses used for non-opportunistic infections suggests that the rate of discontinuation from therapy for laboratory abnormalities is low. In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality. In multiple-dose clinical trials involving almost 3300 pediatric patients, no patients discontinued therapy because of treatmentrelated laboratory abnormalities. (Information from the current product label for 250 mg oral azithromycin.) However, many of the studies of azithromycin included in this submission were of long (sometimes indefinite) duration, and thus the discontinuation rate would be expected to be higher for that reason alone. H.6.H.1 H.6.H.1.A Incidence of Laboratory Abnormalities MAC Studies H.6.H.1.A.1 Pivotal and Primary Supportive Studies H.6.H.1.A.1.A Treatment The following summary table gives the incidence of laboratory abnormalities for all treatment groups in the pivotal and primary supportive studies

5 Page 67 Laboratory Abnormalities - MAC Studies Number (%) of Subjects Azithromycin Clarithromycin 250 mg 500 mg 600 mg 1200 mg 500 mg bid Study Number Total Number of Subjects Lab Parameter (criteria*) Number Abnormal/ Number Evaluable (%) Any Laboratory Abnormality 44/60 (73) 20/26 (77) 25/36 (69) 65/81 (80) 32/45 (71) 53/78 (68) Hemoglobin (<0.8x baseline) 14/54 (26) 7/26 (27) 14/36 (39) 18/75 (24) 9/44 (20) 16/72 (22) Hematocrit (<0.8x baseline) 11/53 (21) 3/26 (12) 13/36 (36) 18/75 (24) 9/44 (20) 14/72 (19) RBC count (<0.75x baseline) 8/54 (15) 3/26 (12) NA 16/75 (21) NA 15/72 (21) Platelets (< /mm 3 ) 3/54 (6) 2/26 (8) 3/36 (8) 4/73 (5) 1/44 (2) 7/71 (10) Platelets (> /mm 3 ) 0/54 (0) 1/26 (4) 0/36 (0) 1/73 (1) 0/44 (0) 1/71 (1) WBC count (< /mm 3 ) 12/54 (22) 5/26 (19) 10/36 (28) 31/75 (41) 10/44 (23) 18/73 (25) WBC Count (> /mm 3 ) 3/54 (6) 0/26 (0) 0/36 (0) 4/75 (5) 0/44 (0) 1/73 (1) Neutrophils (<0.5x LLN) 9/53 (17) 1/26 (4) 3/31 (10) 16/75 (21) 5/38 (13) 9/73 (12) Neutrophils (>1.5x ULN) 4/53 (8) 0/26 (0) 0/31 (0) 7/75 (9) 0/38 (0) 3/73 (4) Eosinophils (>1.5x ULN) 3/53 (6) 0/25 (0) 1/31 (3) 2/75 (3) 0/37 (0) 0/73 (0) Lymphocytes (<0.5x LLN) 9/53 (17) 14/26 (54) 12/31 (39) 22/75 (29) 9/38 (24) 9/73 (12) Lymphocytes (>1.5x ULN) 0/53 (0) 0/26 (0) 0/31 (0) 1/75 (1) 0/38 (0) 0/73 (0) Total bilirubin (>1.5x ULN) 3/59 (5) 1/26 (4) 0/36 (0) 3/79 (4) 0/45 (0) 1/76 (1) Total Protein (<0.8x LLN) 1/9 (11) 0/26 (0) 1/36 (3) 0/18 (0) 0/45 (0) 1/15 (7) Total Protein (>1.2x ULN) 0/9 (0) 0/26 (0) 0/36 (0) 0/18 (0) 1/45 (2) 1/15 (7) Albumin (<0.8x LLN) 12/58 (21) 4/26 (15) 4/36 (11) 13/79 (16) 3/45 (7) 9/76 (12) Albumin (>1.2x ULN) 0/58 (0) 0/26 (0) 0/36 (0) 0/79 (0) 0/45 (0) 0/76 (0) SGOT (>3.0x ULN) 8/59 (14) 0/26 (0) 4/36 (11) 15/79 (19) 5/45 (11) 8/76 (11) SGPT (>3.0x ULN) 4/59 (7) 0/26 (0) 2/36 (6) 10/80 (13) 6/45 (13) 4/77 (5) AP (>3.0x ULN) 8/58 (14) 1/26 (4) 6/36 (17) 16/80 (20) 3/45 (7) 15/77 (19) BUN (>1.3x ULN) 7/59 (12) 2/26 (8) 2/36 (6) 12/81 (15) 2/45 (4) 8/78 (10) Creatinine (>1.3x ULN) 3/59 (5) 1/26 (4) 2/36 (6) 3/81 (4) 2/45 (4) 8/78 (10) Sodium (<0.95x LLN) 0/59 (0) 1/26 (4) 0/36 (0) 2/81 (2) 0/45 (0) 1/77 (1) Sodium (>1.05x ULN) 1/59 (2) 0/26 (0) 0/36 (0) 0/81 (0) 0/45 (0) 1/77 (1) Potassium (<0.9x LLN) 3/58 (5) 0/26 (0) 5/36 (14) 4/81 (5) 0/45 (0) 3/77 (4) Potassium (>1.1x ULN) 1/58 (2) 0/26 (0) 0/36 (0) 0/81 (0) 1/45 (2) 2/77 (3) * Criteria = Primary abnormality criteria (applied to on-treatment laboratory data for subjects with normal baseline). Secondary criteria were used for subjects with abnormal baseline value. NA = Not Applicable Ref: 131-Tables 1.1 and 7.1, 148-Tables 1.1 and 7.1, 189-Tables 1.1 and 7.1 The most common laboratory abnormalities usually were decreased hematocrit, hemoglobin, WBC and lymphocyte counts. Azithromycin 600 mg Dose: In the 600 group for Study 148, the overall rate of laboratory test abnormalities was 25 of 36 subjects (69.4%). The most frequently reported laboratory abnormalities were decreased hemoglobin (14 of 36 subjects, or 38.9%), decreased hematocrit (13 of 36 subjects, or 36.1%) and decreased lymphocytes (12 of 31 subjects, or 38.7%) (148-Table 7.1). Any effect of azithromycin treatment on clinical laboratory tests would be difficult to detect in the pivotal and primary supportive studies, given the high rate of laboratory abnormalities in the study population. Thus, the results of Study 189, which included a clarithromycin comparator arm, are particularly important in elucidating the laboratory safety profile for azithromycin at the dose recommended for treatment of MAC infection. The majority of subjects in both of the treatment groups had at least one laboratory abnormality; i.e., azithromycin 600 mg: 65 of 81 subjects (80.2%) and clarithromycin 500 mg bid, 53 of 78 subjects (67.9%). The most common abnormalities involved hematologic -398-

6 Page 68 and liver function tests. Generally, the incidence of these abnormalities was similar between the two dosing groups with the exception of decreases in WBC count, neutrophils and lymphocytes. These occurred with slightly greater frequency in those subjects receiving azithromycin (189-Table 7.1). Azithromycin at Other Doses: Azithromycin was provided at a dose of 500 mg for 10, 20 or 30 days in Study 131. In the 500 mg treatment phase of Study 131, the most common laboratory test abnormalities predominantly involved hematologic tests, particularly decreases in hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count, and absolute lymphocytes. The incidence of decreased serum albumin was 4 of 26 subjects, or 15.4% (131-Table 7.1). The overall incidence of clinically significant laboratory test abnormalities in the 1200 mg group in Study 148 was 71.1% (32 of 45) of subjects (148-Table 7.1). The most common abnormalities were decreased lymphocytes (9 of 38 subjects, or 23.7%), decreased WBC count (10 of 44 subjects, or 22.7%), decreased hematocrit and hemoglobin (9 of 44 subjects, or 20.4%). The laboratory abnormalities seen in the azithromycin 250 mg treatment arm of Study 189 were similar to those in the study s other treatment regimens. The overall rate of clinically significant abnormalities were 73.3% (44 of 60 subjects).and the most common types of abnormalities involved hematologic and liver function tests (189-Table 7.1). H.6.H.1.A.1.B Maintenance Studies 189 and 131 allowed for continued therapy on a maintenance dose of 250 mg. The maintenance phase of Study 189 is referred to as 189B. Due to differences in the duration of the maintenance phase of these studies data from these studies are discussed separately. Study 131 Ten (10) of the 14 subjects (71.4%) who received 250 mg/day azithromycin in the maintenance phase of Study 131 had at least one laboratory abnormality; the types of abnormalities were mostly hematological and therefore similar to those seen in the treatment phase of the study (131-Table 7.1). Study 189B During extended or suppressive therapy with 250 mg azithromycin, the overall incidence of laboratory abnormalities was 19 of 29 subjects (65.5%). The most common laboratory test abnormalities predominantly involved hematologic and liver function tests. The incidence of decreased lymphocytes was 24% (7 of 29 subjects). The incidence of increased SGPT and the incidence of increased alkaline phosphatase was 17% (5 of 29 subjects) and the incidence of increased BUN was 4 of 29 subjects, or 14% (189-Appendix IA, Table 7.1). H.6.H.1.B Compassionate Use Studies Azithromycin 600 mg Dose: Subjects in Studies 162 and 169 and those being treated for MAC in Study 354/354A were given 600 mg of azithromycin daily (Study 354/354A mg dose on day 1 followed by 600 mg for 27 days). Subjects with inadequate responses could have their dose increased

7 Page 69 The maximum daily dose in Study 162 was 1200 mg, while that in Study 169 was 1500 mg. Laboratory abnormalities for subjects with MAC infections were not analyzed separately for Study 354/354A. Therefore, the laboratory abnormalities for this study are discussed with the non-mac studies below. The overall incidence of laboratory abnormalities among subjects who received oral azithromycin only in Study 162 was 97 of 108 subjects evaluable for laboratory abnormalities, or 90.0%. The most common abnormalities were low lymphocyte count (57 of 105 subjects, or 54.3%), and low WBC (56 of 106 subjects, or 52.8%) respectively (Study 162-Table 7.1). The overall incidence of laboratory abnormalities among subjects who received oral azithromycin only in Study 169 was 18 of 34 subjects (52.9%) evaluable for laboratory abnormalities with decreased lymphocytes the most frequently reported abnormality (5 of 32 subjects, or 15.6%) (169-Table 7.1). Azithromycin 250 mg Intravenously: The overall rate of laboratory abnormalities for subjects who received azithromycin 250 mg intravenous either with or without oral therapy in Study 162 was 19 of 20 subjects (95.0%). Low lymphocyte count (7 of 19 subjects, or 36.8%), decreased hematocrit, hemoglobin, and albumin, and increased SGOT (7 of 20 subjects, or 35.0%) were the most frequently reported laboratory abnormalities (162-Table 7.1). The overall rate of laboratory abnormalities for subjects who received intravenous (with or without oral) azithromycin in Study 169 was 5 of 7 subjects (71.4%). Decreased hematocrit, decreased hemoglobin and increased bilirubin, and increased blood urea nitrogen were reported by two subjects each (169-Table 7.1). Therefore, the laboratory abnormalities observed in the MAC compassionate studies are similar to those described in more detail for the three pivotal and primary supportive studies in the previous section. The majority of the subjects had at least one clinically significant laboratory abnormality, and the most common abnormalities were low or decreased values for hematological and liver function tests. H.6.H.1.C Non-MAC Studies H.6.H.1.C.1 Non-MAC Studies at the 600 mg Dose A 600 mg dose of azithromycin was given in two non-mac studies (354/354A and 167). Please note: Study 354/354A enrolled a mixture of subjects, both MAC and non-mac. Subjects being treated for MAC in Study 354/354A received a 600 mg daily dose of azithromycin, while those with toxoplasmosis received a 1200 mg dose followed by a 600 mg maintenance dose. This section includes laboratory abnormalities for all subjects. The overall incidence of laboratory abnormalities in Study 354/354A was 340 of 522 evaluable subjects (65.1%); with low WBC count the most common laboratory abnormality (155 of 473 subjects, or 32.8%). Decreased hemoglobin was also frequently reported in this large study (127 of 494 subjects, or 25.7%). The rate of elevated SGOT (AST) and elevated SGPT (ALT) was 37 of 324 subjects (11.4%) and 58 of 375 subjects (15.5%), respectively. Relatively few subjects were evaluable for lymphocytes and neutrophils. However, it is interesting to note that the rates of decreased neutrophils and increased neutrophils were similar (9/38 [23.7%] and 11/38 [28.9%], respectively). The rates of decreased lymphocytes and increased lymphocytes were identical (10/40 or 25.0%). Thus, azithromycin treatment did not seem to be associated with a consistent trend in either of these hematological parameters (354/354A-Table 7.1)

8 Page 70 In Study 167, clinically significant laboratory test abnormalities were observed in 77 of 99 (77.8%) evaluable subjects (167-Table 7.1). The most common abnormalities were decreased WBC count (30 of 97 subjects, or 30.9%), increased alkaline phosphatase levels (25 of 98 subjects, or 25.5%), and decreased lymphocytes (22 of 96 subjects, or 22.9%). H.6.H.1.C.2 Non-MAC Studies at doses other than 600 mg: Although the remaining studies of azithromycin in the treatment of opportunistic infections differed considerably from one another in size, design, and type of infection treated, the laboratory abnormalities observed in these studies were consistent with those already presented. The majority of subjects had at least one clinically significant laboratory abnormality, and the most common abnormalities were in hematological tests. H.6.H.1.D Miscellaneous and Terminated Studies The laboratory abnormalities in studies with less than 10 subjects were not summarized. Details of any clinically significant laboratory abnormalities for subjects in these studies can be found, if applicable, in the individual study reports. H.6.H.1.E Phase I Studies The Phase I studies excluded subjects with significant laboratory abnormalities. In three of the studies (086, 088 and 094), laboratory tests were done only at screening. Consequently, no conclusions can be drawn from the very small number of clinically significant laboratory abnormalities observed in these studies. H.6.H.2 Median Changes in Laboratory Parameters Most of the clinical studies analyzed the median changes from baseline for selected laboratory parameters. However, these median changes rarely showed consistent trends among the treatment groups within a single study. For example, the median change for neutrophils in Study 148 decreased for the 24 evaluable subjects in the 600 mg dose group (-0.39 thousand/mm 3 ), but increased for the 27 evaluable subjects in the 1200 mg dose group (+0.48 thousand/ mm 3 ) (148-Table 7.2). There was also no apparent consistency from study to study in these changes. For example, the median change from baseline for neutrophils measured for 69 subjects in the 600 mg azithromycin group in Study 189 was thousand/ mm 3 and the median change from baseline measured for 23 subjects in 354/354A was 0.55 thousand/ mm 3, a 21% increase (189-Table 7.2; 354/354A-Table 7.2). H.6.H.3 Conclusions Previous clinical experience suggests that the rate of laboratory abnormalities associated with azithromycin therapy as recommended for treatment of non-opportunistic infections is low. In multiple-dose clinical trials involving more than 3000 subjects, significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of 1-2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT); with an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate. When follow-up was provided, changes in laboratory tests appeared to be reversible. In pediatric subjects, significant abnormalities (irrespective of drug relationship) occurring during clinical trials were all reported at a frequency of less than 1%, but were similar in type to the adult pattern. (Information from the current product label for 250 mg oral azithromycin.) Among subjects who received azithromycin in the MAC prophylaxis clinical trials, decreased -401-

9 Page 71 hemoglobin, platelet counts, WBC counts, and neutrophils, and elevated SGOT and SGPT were reported with an incidence of 0-8%. In contrast to the low rates of laboratory abnormalities seen in the large database of subjects with non-opportunistic infections (2% or less) and the somewhat higher rates seen in clinical trials of azithromycin in the prophylaxis of MAC infection (<1-8%), the pivotal and primary supportive MAC treatment studies had much higher rates of laboratory abnormalities, in some treatment groups. Note, however, that in some cases, these rates are based on only a small number of abnormalities per treatment group. Also, the higher rates of laboratory abnormalities in these studies may in part result from the effects of MAC infection or AIDS, or to concomitant therapy with drugs such as ethambutol (protocolspecified therapy in 189), or other anti-infectives. In conclusion, the majority of subjects in studies of azithromycin in the treatment of MAC and non-mac opportunistic infections had laboratory abnormalities. Hematological abnormalities were especially frequent. There were also a number of subjects who discontinued azithromycin treatment because of liver function test elevations (see section H.6.C, Premature Discontinuation From the Study). However, it is not possible to associate any specific laboratory abnormalities with azithromycin treatment because many of these subjects had serious underlying or intercurrent illnesses and received a wide variety of concomitant medications. Furthermore, there were no apparent consistent changes from baseline in laboratory test values for azithromycin-treated subjects. H.6.I VITAL SIGNS Although vital signs (pulse, blood pressure, temperature, weight) were measured as specified by the protocol for each study and the results are listed in the individual study reports, no summary tables are included in the individual study reports. Clinical efficacy endpoints in the studies frequently included fever and changes in body weight, but these endpoints were not necessarily based on information recorded on the Vital Signs page(s) of the CRF. These clinical efficacy endpoints were usually collected on the Signs and Symptoms page(s) of the CRF. In studies 148 and 131, however, the change in body weight as captured on the Vital Signs page of the CRF was used as one of the endpoints for clinical efficacy. Changes in vital signs that were analyzed as clinical efficacy endpoints related to changes are discussed in the Overall Summary of Efficacy (snda Section 3.H.4). H.6.J OTHER SPECIAL SAFETY TESTS H.6.J.1 ECG Changes Few studies systematically collected ECG data, and none of the study reports has a summary of ECG data. Collection of post-baseline ECG data was specified by the protocol for Study 147 (toxoplasmic encephalitis), and the report notes individual abnormal ECG findings for the two subjects enrolled in this study as appropriate. H.6.J.2 Audiological Testing In Study 189, patients in some other studies were to have audiograms performed with any suspicion of hearing loss. At the investigator s discretion, audiograms could be obtained for any other auditory complaints. The results of audiological testing from this study are discussed in detail in section H.6.D.4.A of this Overall Summary of Safety Data (Audiological Testing). Protocol-specified audiological testing for all subjects was done in -402-

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