ADVERSE REACTIONS
Because many patients who participated in clinical trials with MEPRON had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by MEPRON from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by MEPRON.
PCP Prevention Studies
In the dapsone comparative study of MEPRON Suspension, adverse experience data were collected only for treatment-limiting events. Among the entire population (n = 1,057), treatment-limiting events occurred at similar frequencies in patients treated with MEPRON Suspension or dapsone (Table 6). Among patients who were taking neither dapsone nor atovaquone at enrollment (n = 487), treatment-limiting events occurred in 43% of patients treated with dapsone and 20% of patients treated with MEPRON Suspension (P <0.001). In both populations, the type of treatment-limiting events differed between the 2 treatment arms. Hypersensitivity reactions (rash, fever, allergic reaction) and anemia were more common in patients treated with dapsone, while gastrointestinal events (nausea, diarrhea, and vomiting) were more common in patients treated with MEPRON Suspension.
Table 6. Treatment-Limiting Adverse Experiences in the Dapsone Comparative PCP Prevention Study
|
Treatment-Limiting
Adverse Experience |
Percentage of Patients with Treatment-Limiting Adverse Experience |
| All Patients |
Patients Not Taking Either Drug at Enrollment |
|
MEPRON
1,500 mg/day
(n = 536) |
Dapsone
100 mg/day
(n = 521) |
MEPRON
1,500 mg/day
(n = 238) |
Dapsone
100 mg/day
(n = 249) |
| Any event |
24.4% |
25.9% |
20.2% |
43.4% |
| Rash |
6.3% |
8.8% |
7.6% |
16.1% |
| Nausea |
4.1% |
0.6% |
2.5% |
0.8% |
| Diarrhea |
3.2% |
0.2% |
2.1% |
0.4% |
| Vomiting |
2.2% |
0.6% |
1.3% |
0.8% |
| Allergic reaction |
1.1% |
2.9% |
0.8% |
4.8% |
| Fever |
0.6% |
2.9% |
0% |
5.6% |
| Anemia |
0% |
1.5% |
0% |
2.0% |
Table 7 summarizes the clinical adverse experiences reported by ≥20% of patients in any group in the aerosolized pentamidine comparative study of MEPRON Suspension (n = 549), regardless of attribution. The incidence of adverse experiences at the recommended dose was similar to that seen with aerosolized pentamidine. Rash was the only individual adverse experience that occurred significantly more commonly in patients treated with both dosages of MEPRON Suspension (39% to 46%) than in patients treated with aerosolized pentamidine (28%). Among patients treated with MEPRON Suspension, there was no evidence of a dose-related increase in the incidence of adverse experiences. Treatment-limiting adverse experiences occurred less often in patients treated with aerosolized pentamidine (7%) than in patients treated with 1,500 mg MEPRON Suspension once daily (25%, P ≤0.001) or 750 mg MEPRON Suspension once daily (16%, P = 0.004). The most common adverse experiences requiring discontinuation of dosing in the group receiving 1,500 mg MEPRON Suspension once daily were rash (6%), diarrhea (4%), and nausea (3%). The most common adverse experience requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%).
Table 7. Treatment-Emergent Adverse Experiences in the Aerosolized Pentamidine Comparative PCP Prevention Study
|
Treatment-Emergent
Adverse Experience |
Percentage of Patients with Treatment-Emergent Adverse Experience |
|
MEPRON
1,500 mg/day
(n = 175) |
MEPRON
750 mg/day
(n = 188) |
Aerosolized
Pentamidine
(n = 186) |
| Diarrhea |
42% |
42% |
35% |
| Rash |
39% |
46% |
28% |
| Headache |
28% |
31% |
22% |
| Nausea |
26% |
32% |
23% |
| Cough increased |
25% |
25% |
31% |
| Fever |
25% |
31% |
18% |
| Rhinitis |
24% |
18% |
17% |
| Asthenia |
22% |
31% |
31% |
| Infection |
22% |
18% |
19% |
| Abdominal pain |
20% |
21% |
20% |
| Dyspnea |
15% |
21% |
16% |
| Vomiting |
15% |
22% |
11% |
| Patients discontinuing therapy due to an adverse experience |
25% |
16% |
7% |
| Patients reporting at least 1 adverse experience |
98% |
96% |
89% |
Other events occurring in ≥10% of the patients receiving the recommended dose of MEPRON included sweating, flu syndrome, pain, sinusitis, pruritus, insomnia, depression, and myalgia. Bronchospasm occurred more frequently in patients receiving aerosolized pentamidine (11%) than in patients receiving MEPRON 1,500 mg/day (4%) and MEPRON 750 mg/day (2%).
Neither MEPRON nor aerosolized pentamidine was associated with a substantial change from baseline values in any measured laboratory parameter, nor were there any significant differences in any measured laboratory parameter between MEPRON and aerosolized pentamidine. Some patients had laboratory abnormalities considered serious by the investigator or that contributed to discontinuation of therapy.
PCP Treatment Studies
Table 8 summarizes all the clinical adverse experiences reported by ≥5% of the study population during the TMP-SMX comparative study of MEPRON (n = 408), regardless of attribution. The incidence of adverse experiences with MEPRON Suspension at the recommended dose was similar to that seen with the tablet formulation of atovaquone.
Table 8. Treatment-Emergent Adverse Experiences in the TMP-SMX Comparative PCP Treatment Study
|
| Percentage of Patients with Treatment-Emergent Adverse Experience |
|
Treatment-Emergent
Adverse Experience |
MEPRON
(n = 203) |
TMP-SMX
(n = 205) |
| Rash (including maculopapular) |
23% |
34% |
| Nausea |
21% |
44% |
| Diarrhea |
19% |
7% |
| Headache |
16% |
22% |
| Vomiting |
14% |
35% |
| Fever |
14% |
25% |
| Insomnia |
10% |
9% |
| Asthenia |
8% |
8% |
| Pruritus |
5% |
9% |
| Monilia, oral |
5% |
10% |
| Abdominal pain |
4% |
7% |
| Constipation |
3% |
17% |
| Dizziness |
3% |
8% |
| Patients discontinuing therapy due to an adverse experience |
9% |
24% |
| Patients reporting at least 1 adverse experience |
63% |
65% |
Although an equal percentage of patients receiving MEPRON and TMP-SMX reported at least 1 adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Twenty-four percent of patients receiving TMP-SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving MEPRON. Four percent of patients receiving MEPRON had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving MEPRON were mild and did not require the discontinuation of dosing. The only other clinical adverse experience that led to premature discontinuation of dosing of MEPRON by more than 1 patient was vomiting (<1%). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%).
Laboratory test abnormalities reported for ≥5% of the study population during the treatment period are summarized in Table 9. Two percent of patients treated with MEPRON and 7% of patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with MEPRON developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX.
Table 9. Treatment-Emergent Laboratory Test Abnormalities in the TMP-SMX Comparative PCP Treatment Study
|
| Percentage of Patients Developing a Laboratory Test Abnormality |
| Laboratory Test Abnormality |
MEPRON |
TMP-SMX |
| Anemia (Hgb<8.0 g/dL) |
6% |
7% |
| Neutropenia (ANC<750 cells/mm3) |
3% |
9% |
| Elevated ALT (>5 x ULN) |
6% |
16% |
| Elevated AST (>5 x ULN) |
4% |
14% |
| Elevated alkaline phosphatase (>2.5 x ULN) |
8% |
6% |
| Elevated amylase (>1.5 x ULN) |
7% |
12% |
| Hyponatremia (<0.96 x LLN) |
7% |
26% |
ULN = upper limit of normal range.
LLN = lower limit of normal range.
Table 10 summarizes the clinical adverse experiences reported by ≥5% of the primary therapy study population (n = 144) during the comparative trial of MEPRON and intravenous pentamidine, regardless of attribution. A slightly lower percentage of patients who received MEPRON reported occurrence of adverse events than did those who received pentamidine (63% vs 72%). However, only 7% of patients discontinued treatment with MEPRON due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (P <0.001). Of the 5 patients who discontinued therapy with MEPRON, 3 reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of MEPRON was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%).
Table 10. Treatment-Emergent Adverse Experiences in the Pentamidine Comparative PCP Treatment Study (Primary Therapy Group)
|
| Percentage of Patients with Treatment-Emergent Adverse Experience |
|
Treatment-Emergent
Adverse Experience |
MEPRON
(n = 73) |
Pentamidine
(n = 71) |
| Fever |
40% |
25% |
| Nausea |
22% |
37% |
| Rash |
22% |
13% |
| Diarrhea |
21% |
31% |
| Insomnia |
19% |
14% |
| Headache |
18% |
28% |
| Vomiting |
14% |
17% |
| Cough |
14% |
1% |
| Abdominal pain |
10% |
11% |
| Pain |
10% |
10% |
| Sweat |
10% |
3% |
| Monilia, oral |
10% |
3% |
| Asthenia |
8% |
14% |
| Dizziness |
8% |
14% |
| Anxiety |
7% |
10% |
| Anorexia |
7% |
10% |
| Sinusitis |
7% |
6% |
| Dyspepsia |
5% |
10% |
| Rhinitis |
5% |
7% |
| Taste perversion |
3% |
13% |
| Hypoglycemia |
1% |
15% |
| Hypotension |
1% |
10% |
| Patients discontinuing therapy due to an adverse experience |
7% |
41% |
| Patients reporting at least 1 adverse experience |
63% |
72% |
Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 11. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 patients who received MEPRON. One patient (1%) had elevated creatinine and BUN levels and 1 patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%), and leukopenia (4%).
Table 11. Treatment-Emergent Laboratory Test Abnormalities in the Pentamidine Comparative PCP Treatment Study
| Laboratory Test |
Percentage of Patients Developing a Laboratory Test Abnormality |
| Abnormality |
MEPRON |
Pentamidine |
| Anemia (Hgb<8.0 g/dL) |
4% |
9% |
| Neutropenia (ANC<750 cells/mm3) |
5% |
9% |
| Hyponatremia (<0.96 x LLN) |
10% |
10% |
| Hyperkalemia (>1.18 x ULN) |
0% |
5% |
| Alkaline phosphatase (>2.5 x ULN) |
5% |
2% |
| Hyperglycemia (>1.8 x ULN) |
9% |
13% |
| Elevated AST (>5 x ULN) |
0% |
5% |
| Elevated amylase (>1.5 x ULN) |
8% |
4% |
| Elevated creatinine (>1.5 x ULN) |
0% |
7% |
ULN = upper limit of normal range.
LLN = lower limit of normal range.
Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of MEPRON. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to MEPRON.
Blood and Lymphatic System Disorders
Methemoglobinemia, thrombocytopenia.
Immune System Disorders
Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, and urticaria.
Eye Disorders
Vortex keratopathy.
Gastrointestinal Disorders
Pancreatitis.
Hepatobiliary Disorders
Rare cases of hepatitis, and one case of fatal liver failure have been reported with atovaquone usage.
Skin and Subcutaneous Tissue Disorders
Erythema multiforme, Stevens-Johnson syndrome, and skin desquamation have been reported in patients receiving multiple drug therapy including atovaquone.
Renal and Urinary Disorders
Acute renal impairment.
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