Pharmacy & Therapeutics - March 2008 - (Page 136) DRUG FORECAST ADVERSE DRUG REACTIONS7,9–13 Safety and adverse reactions associated with doripenem are best summarized from pooled data from three pivotal phase 3 studies. The studies included a total of 853 adults who were treated with doripenem for complicated UTIs or complicated intra-abdominal infections. The most common adverse reactions observed were headache, nausea, diarrhea, rash, and phlebitis. These reactions occurred in 5% of patients or more; this rate was generally comparable to the control groups’ use of levofloxacin or meropenem. Additional adverse dr ug re actions reported 1% of the time or more included anemia, hepatic enzyme elevations, and mycotic infections. The rate of discontinuation of doripenem because of adverse effects was extremely low: 0.2%, from nausea, 0.1%, from vulvomycotic infection; and 0.1%, from rash. Rare adverse effects (at a rate below 1%) in the analysis included hypersensitivity reactions and Clostridium dif ficile colitis. Voluntarily reported, postmarketing safety data from outside the U.S. has also included cases of anaphylaxis, severe rash, including Stevens–Johnson syndrome or toxic epidermal necrolysis, and seizures with the use of doripenem. However, the true frequency has not been established because of data limitations. Two additional phase 3 studies (DORI9 and DORI-10) of nosocomial pneumonia, including ventilator-associated pneumonia, did attempt to quantify the frequency of seizures with doripenem, compared with standard therapy. In these studies, seizures occurred less frequently with doripenem than with piperacillin/ tazobactam (1.3% vs. 2.7%) and when compared with imipenem (1.1% vs. 3.8%) at standard doses. tubular secretion of doripenem, resulting in increased plasma concentrations. Carbapenems, as documented in the literature, can lead to significantly reduced serum valproic acid concentrations, which may result in loss of seizure control. Although the mechanism of this interaction is not fully understood, in vitro and animal studies suggest that carbapenems might inhibit valproic acid glucuronide hydrolysis or the valproic acid intestinal transporter necessary for absorption. Ortho-McNeil recommends frequent monitoring of serum valproic acid levels after doripenem therapy begins or consideration of an alternative antibacterial or anticonvulsive agent if therapeutic serum valproic acid concentrations cannot be maintained or if a seizure occurs. ing the carbapenems, doripenem has been linked to C. dif ficile–associated diarrhea because of its potential to significantly alter the normal colonic flora. This may permit the overgrowth of C. difficile, especially in severely ill hospitalized patients; these are the patients most likely to receive doripenem. For this reason and because of the potential emergence of resistance to doripenem, this agent should be used judiciously for documented bacterial infections. Pneumonitis has also been observed with inhaled doripenem; therefore, this medication should not be given via the inhalation route. DOSAGE AND ADMINISTRATION7–9 In patients 18 years of age and older, the recommended dosage for doripenem is 500 mg every eight hours, given as an IV infusion over one hour. Dosage adjustments are necessary in patients with renal insufficiency if the creatinine clearance (CrCl) falls below 50 mL/minute. The recommended dosage of doripenem for a CrCl between 30 and 50 mL/minute is 250 mg IV, given over one hour every eight hours; the dosage for a CrCl between 10 and 30 mL/minute is 250 mg IV given over one hour every 12 hours. Doripenem is available in single-use clear glass vials; it must be reconstituted and diluted with either 0.9% sodium chloride or 5% dextrose. After preparation, products prepared in 0.9% sodium chloride or 5% dextrose are stable at room temperature for eight hours and four hours, respectively. When refrigerated, prepared doripenem is stable for 24 hours regardless of the solution in which it is prepared. The duration of therapy varies according to the drug’s indication. For complicated intra-abdominal infections, it is recommended for five to 14 days; for complicated UTIs (including pyelonephritis), the duration of therapy is typically for 10 days, although it may be extended to 14 days for concurrent bacteremia. CONTRAINDICATIONS7–9,17 Doripenem is not indicated for patients with a known serious hypersensitivity to doripenem or other carbapenems. It should not be used in patients with a histor y of an anaphylactic reaction to beta-lactam antibiotics because of crossreactivity; this has been clearly documented in the literature. PRECAUTIONS AND WARNINGS7–9 Appropriate precautions should be taken before doripenem therapy is initiated, because serious and occasionally fatal hypersensitivity and serious skin reactions, such as Stevens–Johnson syndrome or toxic epidermal necrolysis, may occur in patients receiving betalactam antibiotics. A thorough history of the severity and type of hypersensitivity reaction to carbapenems, penicillins, cephalosporins, or other allergens should be obtained before patients start doripenem therapy, because cross-reactivity with beta-lactam antibiotics has been documented. If hypersensitivity develops, doripenem should be discontinued and an alternative therapy should be initiated. Renal function should be assessed before patients begin therapy and during the course of therapy, because the drug may accumulate, resulting in varied degrees of renal impairment. Medication profiles of patients should also be screened for potential drug interactions. As with most antibiotics, includ- DRUG INTERACTIONS7,8,14–16 The fact that no metabolism of doripenem was detected in vitro utilizing pooled human microsomes suggests that doripenem is not a substrate for hepatic cytochrome P-450 (CYP 450) enzymes. It is therefore unlikely that doripenem has any drug interactions via the CYP 450 system by enzyme induction or inhibition. Doripenem is eliminated unchanged primarily via the kidneys; hence, the concurrent use of probenecid is not recommended because it interferes with active CONCLUSION As the most recently approved agent in its class, doripenem (Doribax) is a promising agent with a spectrum of activity similar to that of meropenem against gram-negative bacteria and similar to imipenem against gram-positive bacteria. continued on page 180 136 P&T® • March 2008 • Vol. 33 No. 3
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