ADVERSE REACTIONS
The investigators in the tuberculosis treatment clinical trial (Study 008) assessed the causality of adverse events as definitely, probably, possibly, unlikely or not related to one of the two drug regimens tested. The following table (Table 2-3) presents treatment-related adverse events deemed by the investigators to be at least possibly related to any of the four drugs in the regimens (rifapentine/rifampin, isoniazid, pyrazinamide, or ethambutol) which occurred in ≥1% of patients. Hyperuricemia was the most frequently reported event that was assessed as treatment related and was most likely related to the pyrazinamide since no cases were reported in the Continuation Phase when this drug was no longer included in the treatment regimen.
Table 2-3. Treatment-Related Adverse Events Occurring in ≥1% of the Patients in Study 008 | Intensive Phase Intensive Phase consisted of therapy with either rifapentine or rifampin combined with isoniazid, pyrazinamide, and ethambutol administered daily (rifapentine twice weekly) for 60 days. | Continuation Phase Continuation Phase consisted of therapy with either rifapentine or rifampin combined with isoniazid for 120 days. Rifapentine patients were dosed once weekly; rifampin patients were dosed twice weekly. Events recorded in this phase includes those reported up to 3 months after Continuation Phase therapy was completed. | Total |
Preferred Term | Rifapentine Combination (N=361) N (%) | Rifampin Combination (N=361) N (%) | Rifapentine Combination (N=321) N (%) | Rifampin Combination (N=307) N (%) | Rifapentine Combination (N=361) N(%) | Rifampin Combination (N=361) N (%) |
Note: ≥1% refers to rifapentine in the TOTAL column. |
Note: A patient may have experienced the same adverse event more than once during the course of the study, therefore, patient counts across the columns may not equal the patient counts in the TOTAL column. |
Hyperuricemia | 78 (21.6) | 55 (15.2) | 0 | 0 | 78 (21.6) | 55 (15.2) |
ALT increased | 12 (3.3) | 17 (4.7) | 6 (1.9) | 7 (2.3) | 18 (5.0) | 24 (6.6) |
AST increased | 11 (3.0) | 16 (4.4) | 5 (1.6) | 7 (2.3) | 15 (4.2) | 23 (6.4) |
Neutropenia | 7 (1.9) | 9 (2.5) | 12 (3.7) | 9 (2.9) | 18 (5.0) | 18 (5.0) |
Pyuria | 11 (3.0) | 10 (2.8) | 6 (1.9) | 3 (1.0) | 14 (3.9) | 12 (3.3) |
Proteinuria | 15 (4.2) | 10 (2.8) | 2 (0.6) | 1 (0.3) | 17 (4.7) | 11 (3.0) |
Hematuria | 10 (2.8) | 12 (3.3) | 4 (1.2) | 4 (1.3) | 13 (3.6) | 15 (4.2) |
Lymphopenia | 14 (3.9) | 13 (3.6) | 3 (0.9) | 1 (0.3) | 16 (4.4) | 14 (3.9) |
Urinary casts | 11 (3.0) | 3 (0.8) | 4 (1.2) | 0 | 14 (3.9) | 3 (0.8) |
Rash | 9 (2.5) | 19 (5.3) | 4 (1.2) | 3 (1.0) | 13 (3.6) | 21 (5.8) |
Pruritus | 8 (2.2) | 15 (4.2) | 1 (0.3) | 1 (0.3) | 9 (2.5) | 16 (4.4) |
Acne | 5 (1.4) | 3 (0.8) | 2 (0.6) | 1 (0.3) | 7 (1.9) | 4 (1.1) |
Anorexia | 6 (1.7) | 8 (2.2) | 3 (0.9) | 4 (1.3) | 8 (2.2) | 10 (2.8) |
Anemia | 7 (1.9) | 9 (2.5) | 2 (0.6) | 1 (0.3) | 9 (2.5) | 10 (2.8) |
Leukopenia | 4 (1.1) | 4 (1.1) | 3 (0.9) | 5 (1.6) | 7 (1.9) | 8 (2.2) |
Arthralgia | 9 (2.5) | 7 (1.9) | 0 | 0 | 9 (2.5) | 7 (1.9) |
Pain | 7 (1.9) | 5 (1.4) | 0 | 1 (0.3) | 7 (1.9) | 6 (1.7) |
Nausea | 7 (1.9) | 2 (0.6) | 0 | 1 (0.3) | 7 (1.9) | 3 (0.8) |
Vomiting | 4 (1.1) | 6 (1.7) | 1 (0.3) | 1 (0.3) | 5 (1.4) | 7 (1.9) |
Headache | 3 (0.8) | 4 (1.1) | 1 (0.3) | 3 (1.0) | 4 (1.1) | 7 (1.9) |
Dyspepsia | 3 (0.8) | 5 (1.4) | 2 (0.6) | 3 (1.0) | 4 (1.1) | 8 (2.2) |
Hypertension | 3 (0.8) | 0 (0.0) | 1 (0.3) | 1 (0.3) | 4 (1.1) | 1 (0.3) |
Dizziness | 4 (1.1) | 0 | 0 | 1 (0.3) | 4 (1.1) | 1 (0.3) |
Thrombocytosis | 4 (1.1) | 2 (0.6) | 0 | 0 | 4 (1.1) | 2 (0.6) |
Diarrhea | 4 (1.1) | 0 | 0 | 0 | 4 (1.1) | 0 |
Rash maculopapular | 4 (1.1) | 3 (0.8) | 0 | 0 | 4 (1.1) | 3 (0.8) |
Hemoptysis | 2 (0.6) | 0 | 2 (0.6) | 0 | 4 (1.1) | 0 |
Treatment-related adverse events of moderate or severe intensity in <1% of the rifapentine combination therapy patients in Study 008 are presented below by body system.
Hepatic & Biliary: bilirubinemia, hepatitis
Dermatologic: urticaria, skin discoloration
Hematologic: thrombocytopenia, neutrophilia, leukocytosis, purpura, hematoma
Metabolic & Nutritional: hyperkalemia, hypovolemia, alkaline phosphatase increased, LDH increased
Body as a Whole - General: peripheral edema, fatigue
Gastrointestinal: constipation, esophagitis, gastritis, pancreatitis
Musculoskeletal: gout, arthrosis
Psychiatric: aggressive reaction
Three patients (two rifampin combination therapy patients and one rifapentine combination therapy patient) were discontinued in the Intensive Phase as a result of hepatitis with increased liver function tests (ALT, AST, LDH, and bilirubin). Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. The two rifampin patients and one rifapentine patient recovered without sequelae.
Twenty-two deaths occurred in Study 008 (eleven in the rifampin combination therapy group and eleven in the rifapentine combination therapy group). None of the deaths were attributed to study medication. In the study, 18/361 (5.0%) rifampin combination therapy patients discontinued the study due to an adverse event compared to 11/361 (3.0%) rifapentine combination therapy patients.
The overall occurrence rate of treatment-related adverse events was higher in males with the rifapentine combination regimen (50%) versus the rifampin combination regimen (43%), while in females the overall rate was greater in the rifampin combination group (68%) compared to the rifapentine combination group (59%). However, there were higher frequencies of treatment-related hematuria and ALT increases for female patients in both treatment groups compared to those for male patients.
Adverse events associated with rifampin may occur with rifapentine: effects of enzyme induction to increase metabolism resulting in decreased concentration of endogenous substrates, including adrenal hormones, thyroid hormones, and vitamin D.
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