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The following adverse reactions are discussed in greater detail in other sections of labeling:

• Anaphylaxis and serious hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
• Interaction with sodium valproate [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
• Clostridium difficile-associated diarrhea [see WARNINGS AND PRECAUTIONS]
• Development of drug-resistant bacteria [see WARNINGS AND PRECAUTIONS]
• Pneumonitis with inhalational use [see WARNINGS AND PRECAUTIONS]

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, 853 adult patients were treated with DORIBAX® IV (500 mg administered over 1 hour every 8 hours) in the three comparative phase 3 clinical studies; in some patients, parenteral therapy was followed by a switch to an oral antimicrobial. [see Clinical Studies] The median age of patients treated with DORIBAX® was 54 years (range 18–90) in the comparative cUTI study and 46 years (range 18–94) in the pooled comparative cIAI studies. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63%) in the pooled cIAI studies. The patients treated with DORIBAX® were predominantly Caucasian (77%) in the three pooled phase 3 studies.

The most common adverse reactions ( ≥ 5%) observed in the DORIBAX® phase 3 clinical trials were headache, nausea, diarrhea, rash and phlebitis. During clinical trials, adverse drug reactions that led to DORIBAX® discontinuation were nausea (0.2%), vulvomycotic infection (0.1%) and rash (0.1%).

Adverse reactions due to DORIBAX® 500 mg administered every 8 hours that occurred at a rate ≥ 1 % in either indication are listed in Table 4. Hypersensitivity reactions related to intravenous study drug and C. difficile colitis occurred at a rate of less than 1% in the three controlled phase 3 clinical trials.

Table 4: Adverse Reactions* with Incidence Rates (%) of ≥ 1% and Adverse Events^†Having Clinically Important Differences in Frequency by Indication in the Three Controlled, Comparative DORIBAX® Phase 3 Clinical Trials

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.

Anaphylaxis
Neutropenia
Leukopenia
Thrombocytopenia
Toxic epidermal necrolysis, Stevens-Johnson Syndrome

The following treatment-emergent adverse events (known to occur with beta-lactams including carbapenems) have been reported voluntarily during post-approval use of DORIBAX®. They are included due to their seriousness, although it is not possible to estimate their frequency and causality has not been established:

Interstitial pneumonia
Seizure

Valproic Acid

Co-administration of DORIBAX® with valproic acid causes the serum concentrations of valproic acid to fall below the therapeutic range, increasing the risk for breakthrough seizures. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that doripenem may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the plasma concentrations of valproic acid. This is consistent with case reports for other carbapenems, where serum concentrations of valproic acid were reduced upon co-administration with a carbapenem. If administration of DORIBAX® is necessary, supplemental anti-convulsant therapy should be considered. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid. [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]

Probenecid

Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations of doripenem. [see CLINICAL PHARMACOLOGY] Coadministration of probenecid with DORIBAX® is not recommended.

Last reviewed on RxList: 2/16/2012
This monograph has been modified to include the generic and brand name in many instances.