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Doribax
Classes
Carbapenems
Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Diluted infusion solutions of doripenem range in color from clear, colorless solutions to solutions that are clear and slightly yellow. Color variations in this range do not affect potency.
Administer intravenously.
Reconstitution
Doripenem does not contain a bacteriostatic preservative; observe aseptic technique while preparing the infusion solution.
500-mg dose using the 500 mg vial: Constitute the vial with 10 mL of sterile water for injection or sodium chloride 0.9% (normal saline). Gently shake to form a suspension. The resultant concentration is 50 mg/mL. THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION; FURTHER DILUTION IS REQUIRED. Using a syringe with a 21-gauge needle, withdraw the suspension and add it to an infusion bag containing 100 mL of normal saline or 5% Dextrose injection; gently shake until clear. The final infusion solution will have a concentration of 4.5 mg/mL.
250-mg dose using the 500 mg vial: Constitute the vial with 10 mL of sterile water for injection or sodium chloride 0.9% (normal saline). Gently shake to form a suspension. The resultant concentration is 50 mg/mL. THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION; FURTHER DILUTION IS REQUIRED. Using a syringe with a 21-gauge needle, withdraw the suspension and add it to an infusion bag containing 100 ml of normal saline or 5% Dextrose injection; gently shake until clear. Remove 55 mL of this solution from the bag and discard. The remaining infusion solution contains 250 mg doripenem at a concentration of 4.5 mg/mL.
250-mg dose using the 250 mg vial: Constitute the vial with 10 mL of sterile water for injection or sodium chloride 0.9% (normal saline). Gently shake to form a suspension. The resultant concentration is 25 mg/mL. THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION; FURTHER DILUTION IS REQUIRED. Using a syringe with a 21-gauge needle, withdraw the suspension and add it to an infusion bag containing 50 or 100 mL of normal saline or 5% Dextrose injection; gently shake until clear. The final infusion solution will have a concentration of 4.2 mg/mL (50 mL infusion bag) or 2.3 mg/mL (100 mL infusion bag).
Storage: Constituted suspensions may be held in vial for up to 1 hour prior to transfer and dilution in the infusion bag. Including storage and infusion time, diluted infusion solutions are stable for up to 12 hours in normal saline or 4 hours in 5% Dextrose injection at controlled room temperature of 15—25 degrees C (59—77 degrees F). Diluted infusion solutions are stable for up to 72 hours in normal saline or 24 hours in 5% Dextrose injection under refrigeration at 2—8 degrees C (36—46 degrees F). Do not freeze constituted solutions.
If Baxter Minibag Plus infusion bags are to be used, consult the instructions provided by the infusion bag manufacturer.
Intravenous Infusion
Do not mix with or physically add to solutions containing other drugs. Compatibility with other drugs has not been established.
Infuse IV over 1 hour.
Extended Stability Studies
In a stability study, doripenem vials were reconstituted and mixed with either 0.9% sodium chloride (normal saline) or 5% Dextrose injection to produce 100 mL solutions at concentrations of either 5 mg/mL or 10 mg/mL in both PVC bags or elastomeric pumps. Both concentrations were stable for 24 hours in normal saline and 16 hours in 5% Dextrose injection at room temperature (25 degrees C). When refrigerated (4 degrees C), all 5 mg/mL solutions were stable for at least 10 days and all 10 mg/mL solutions were stable for at least 7 days. All solutions were stable for 16 hours when previously frozen and thawed at 25 and 4 degrees C. The rate of degradation was similar between PVC and elastomeric containers.
In a study reviewing stability at temperatures higher than normally defined room temperature (25 degrees C), doripenem vials were reconstituted with 10 mL of normal saline and diluted in 90 mL of normal saline to produce 5 mg/mL solutions. At 30 degrees C, it was stable for 16 hours. At 35 degrees C, it was stable for 12 hours. At 40 degrees C, it was stable for 8 hours.
In a stability study for administration by continuous infusion, vials were reconstituted with sterile water at a concentration of 1 g/100 mL. Doripenem was stable for 24 hours at 25 degrees C and approximately 12 hours at 37 degrees C.
In a stability study, vials were reconstituted to a 5 mg/mL concentration in either normal saline or 5% Dextrose injection in PVC bags, PVC bags with vial adapter, and polyethylene bags and assessed at room temperature (25 degrees C) or refrigeration (5 decrees C). Doripenem was stable for 12 hours at room temperature and 72 hours when refrigerated in normal saline and for 4 hours at room temperature and 48 hours when refrigerated in 5% Dextrose injection.
Adverse Reactions
anaphylactoid reactions / Rapid / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
seizures / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
anemia / Delayed / 2.0-10.0
phlebitis / Rapid / 4.0-8.0
elevated hepatic enzymes / Delayed / 1.0-2.0
candidiasis / Delayed / 1.0-1.0
neutropenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
pseudomembranous colitis / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
headache / Early / 4.0-16.0
nausea / Early / 4.0-12.0
diarrhea / Early / 6.0-11.0
rash / Early / 1.0-5.0
Common Brand Names
Doribax
Dea Class
Rx
Description
IV broad spectrum carbapenem antibiotic
For complicated intraabdominal and urinary tract infections in adults
Spectrum of activity similar to imipenem and meropenem but is more active in vitro against Pseudomonas aeruginosa
Dosage And Indications
500 mg IV every 8 hours for 5 to 14 days. If clinical improvement is evident after at least 3 days, consider a switch to an appropriate oral therapy. Clinical practice guidelines recommend doripenem for 4 to 7 days for severe or high-risk community-acquired infections or complicated health-care associated infections.
500 mg IV every 8 hours for 10 days; duration may be extended up to 14 days for patients with concurrent bacteremia. If clinical improvement is evident after at least 3 days of IV doripenem, a switch to an appropriate oral therapy may be considered.
500 mg IV every 8 hours is used for other indications. Start within 1 hour of recognition as part of empiric multi-drug therapy. Duration of therapy is generally 7 to 10 days, but may be shorter or longer depending upon patient response, site of infection, and pathogen(s) isolated. Treatment may be narrowed with pathogen identification and/or adequate clinical response.
†Indicates off-label use
Dosing Considerations
No dosage adjustment is needed.
CrCl more than 50 mL/minute: No dose adjustment needed.
CrCl 30 to 50 mL/minute: 250 mg IV every 8 hours.
CrCl 11 to 29 mL/minute: 250 mg IV every 12 hours.
CrCl 10 mL/minute or less: Dosage adjustment recommendations are not available due to insufficient data.
Intermittent hemodialysis
Doripenem is hemodialyzable; however, dosage adjustment recommendations are not available due to insufficient data.
Continuous renal replacement therapy (CRRT)
In an observational pharmacokinetic study in 12 critically ill adult patients undergoing continuous venovenous hemodiafiltration (CVVHDF), doripenem 500 mg IV every 8 hours maintained concentrations above the MIC for at least 40% of the dosing interval (T > MIC 40% or more) for organisms with an MIC of 4 mg/L or less. Doripenem clearance was significantly correlated with the replacement fluid flow rate and accounted for approximately 30% to 37% of the total clearance. The median replacement fluid rate was 1000 mL/hour (1000 to 2000 mL/hour), with the CVVHDF remaining uninterrupted during each dosing interval. The CL was 1.34 L/hour for a flow rate of 1000 mL/hour and 1.84 L/hour for a flow rate of 2000 mL/hour.
Drug Interactions
Colchicine; Probenecid: (Moderate) Probenecid inhibits the renal excretion of doripenem by competing with doripenem for active tubular secretion. The elimination half-life of doripenem is increased by 53% and the extent of systemic exposure (AUC) to doripenem is increased by 75%. Concurrent administration of doripenem with probenecid is not recommended.
Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Probenecid: (Moderate) Probenecid inhibits the renal excretion of doripenem by competing with doripenem for active tubular secretion. The elimination half-life of doripenem is increased by 53% and the extent of systemic exposure (AUC) to doripenem is increased by 75%. Concurrent administration of doripenem with probenecid is not recommended.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
Valproic Acid, Divalproex Sodium: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations.
Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
How Supplied
Doribax/Doripenem Intravenous Inj Pwd F/Sol: 250mg, 500mg
Maximum Dosage
500 mg IV every 8 hours.
500 mg IV every 8 hours.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Mechanism Of Action
Doripenem inhibits cell wall formation, facilitates bacterial cell lysis, and is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. PBP-1 is responsible for formation of the cell wall; PBP-2 is responsible for maintaining the rod-like shape; and PBP-3 is responsible for bacterial septum formation. Other PBPs have been identified but are not primary sites of action for beta-lactams.
Pharmacokinetics
Doripenem is administered intravenously as an infusion over 1 hour. Doripenem is distributed into most body fluids and tissues, including bile, gallbladder, peritoneal exudate, retroperitoneal fluid, and urine. Peritoneal and retroperitoneal fluid concentrations either match or exceed the MICs of most susceptible bacteria. Plasma protein binding is approximately 8.1%. It is minimally metabolized to one microbiologically inactive ring-opened metabolite (doripenem-M1) via dehydropeptidase-I. Hepatic CYP enzymes are not involved in the metabolism of doripenem. Excretion is mainly as unchanged drug in the urine, with approximately 70% of the dose recovered over 48 hours. About 15% of the dose is recovered in the urine as the metabolite. In patients with normal renal function, the elimination half-life is approximately 1 hour.
Mean doripenem peak plasma concentrations after a 500-mg single IV dose to healthy subjects are approximately 23 mcg/mL. Accumulation does not occur following multiple doses of 500 mg or 1 g IV every 8 hours for 7—10 days in patients with normal renal function.
Pregnancy And Lactation
According to the manufacturer, doripenem is classified pregnancy category B. Safe use during human pregnancy has not been established. Although adequate and well-controlled studies have not been performed in humans, no teratogenic effects have been demonstrated in animal studies. Although it is unknown if doripenem crosses the placenta, its low molecular weight, negligible metabolism, and low protein binding would suggest that doripenem likely crosses the placental barrier. Use during pregnancy only if clearly needed.
According to the manufacturer, it is not known whether doripenem is excreted in human breast milk. However, low molecular weight, negligible metabolism, and low protein binding would suggest that doripenem is excreted into breast milk. While the effect on a nursing infant is unknown, potential problems could include bowel flora modification as well as direct effects, such as an allergic reaction. In general, unless the infant is allergic to doripenem, breast-feeding is likely safe during maternal carbapenem therapy; the infant should be observed for potential effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences and adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.