DORIBAX SIDE EFFECTS
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of labeling:
- Anaphylaxis and serious hypersensitivity reactions.
- Seizures.
- Interaction with sodium valproate.
- Clostridium difficile-associated diarrhea.
- Development of drug-resistant bacteria.
- Pneumonitis with inhalational use.
Adverse Reactions From Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.
During clinical investigations, 1338 adult patients were treated with DORIBAX® (1076 patients received doripenem 500 mg administered over 1 hour every 8 hours and 262 patients received doripenem 500 mg administered over 4 hours every 8 hours); in some patients parenteral therapy was followed by a switch to an oral antimicrobial. The median age of patients treated with DORIBAX® was 54 years (range 18– 90) in the comparative complicated urinary tract infections (cUTI) study, 46 years (range 18–94) in the pooled comparative complicated intra-abdominal infections (cIAI) studies, and 56 years (range 18-94) in the other Phase 3 trials. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63% and 75%) in the comparative cIAI and other Phase 3 trials, respectively. The patients treated with DORIBAX® were predominantly Caucasian (79%) in the five comparator-controlled Phase 3 studies.
The most common adverse drug reactions ( ≥ 5%) observed in the five DORIBAX® comparator-controlled Phase 3 clinical trials were anemia, headache, nausea, diarrhea, rash, phlebitis, and elevated hepatic enzymes. During clinical trials, adverse events led to discontinuation of DORIBAX® in 4.1% (55 of 1338) of patients compared to 4.3% (58 of 1325) of comparator-treated patients.
Adverse reactions due to DORIBAX® 500 mg every 8 hours that occurred at a rate ≥ 1 % are listed in Table 1. Hypersensitivity reactions related to intravenous study drug occurred at a rate of less than 1%.
Table 1: Adverse Reactions with Incidence Rates (%) of ≥ 1% in the Controlled Phase 3 Clinical Trials
| System organ class | Complicated Urinary Tract Infections (one trial) | Complicated Intra Abdominal Infections (two trials) | Other Phase 3 Trials (two trials) | |||
| DORIBAX® 500 mg administered every 8 hours (n =376 ) |
Levofloxacin 250 mg administered IV every 24 hours (n = 372) |
DORIBAX® 500 mg administered every 8 hours (n = 477) |
Meropenem 1 g administered every 8 hours (n = 469) |
DORIBAX® 500 mg administered every 8 hours (n =485 ) |
Comparator* (n=484) |
|
| Nervous system disorders | ||||||
| Headache | 16 | 15 | 4 | 5 | 3 | 3 |
| Vascular disorders | ||||||
| Phlebitis | 4 | 4 | 8 | 6 | 2 | 1 |
| Gastro-intestinal disorders | ||||||
| Nausea | 4 | 6 | 12 | 9 | 7 | 7 |
| Diarrhea | 6 | 10 | 11 | 11 | 12 | 14 |
| C. difficile colitis | < 1 | 0 | < 1 | 0 | 1 | 2 |
| Blood and Lymphatic System Disorders | ||||||
| Anemia | 2 | 1 | 10 | 5 | 5 | 6 8 |
| Skin and subcutaneous disorders | ||||||
| Pruritus | 1 | 1 | 3 | 2 | 1 | 1 |
| Rash | 1 | 1 | 4 | 2 | 6 | 5 |
| Investigations | ||||||
| Hepatic Enzyme elevation** | 2 | 4 | 2 | 4 | 7 | 6 |
| Infections and Infestations | ||||||
| Oral candidiasis | 1 | 0 | 1 | 2 | 3 | 1 |
| Vulvomycotic infection | 2 | 1 | 1 | < 1 | 0 | < 1 |
| * Comparators include piperacillin/tazobactam (4.5 g every 8 hours) and imipenem (500 mg every 6 hours or 1 g every 8 hours) ** including preferred terms (alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased) and laboratory test values (ALT or AST ≤ ULN at baseline and > 5 x ULN at End of Treatment (EOT)) |
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In a Phase 1 study of healthy subjects receiving doripenem doses greater than the approved dose of 500 mg every 8 hours for 10 to 14 days, the incidence of rash was higher than that observed in subjects who received 500 mg every 8 hours. The rash resolved within 10 days after doripenem administration was discontinued.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of doripenem. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hematologic: Leukopenia, Neutropenia, Thrombocytopenia
Immune System: Anaphylaxis
Nervous System: Seizure
Renal: Renal impairment/failure
Respiratory: Interstitial pneumonia
Skin: Toxic epidermal necrolysis, Stevens-Johnson Syndrome
SRC: NLM .