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DORIBAX® (doripenem) powder, for solution

DESCRIPTION CLINICAL PHARMACOLOGY INDICATIONS AND USAGE
CONTRAINDICATIONS PRECAUTIONS ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION HOW SUPPLIED  
PRESCRIBING HIGHLIGHTS:  Please see package insert for additional information and possible updates to ensure safe and effective use of this medication. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. Please read the disclaimer carefully BEFORE accessing or using this site. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.  
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(DESCRIPTION) top of page

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DORIBAX safely and effectively. See full prescribing information for DORIBAX.

DORIBAX (doripenem) Powder, For Solution for Intravenous use
Initial U.S. Approval: 2007

DESCRIPTION

DORIBAX®, doripenem monohydrate for injection vials contain 500 mg of doripenem on an anhydrous basis, a white to slightly-yellowish off-white sterile crystalline powder. All references to doripenem activity are expressed in terms of the active doripenem moiety. The powder is constituted for intravenous infusion. The pH of the infusion solution is between 4.5 and 5.5.

DORIBAX® is not formulated with any inactive ingredients.

CLINICAL PHARMACOLOGY: top of page

CLINICAL PHARMACOLOGY

Doripenem is a carbapenem with in vitro antibacterial activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria.

Mechanism of Action
Doripenem is an antibacterial drug.
Microbiology
Doripenem belongs to the carbapenem class of antimicrobials. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.

Mechanism(s) of Resistance
Bacterial resistance mechanisms that affect doripenem include drug inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, with the exception of carbapenem hydrolyzing beta-lactamases. Although cross-resistance may occur, some isolates resistant to other carbapenems may be susceptible to doripenem.

Interaction with Other Antimicrobials
In vitro synergy tests with doripenem show doripenem has little potential to antagonize or be antagonized by other antibiotics (e.g., levofloxacin, amikacin, trimethoprim-sulfamethoxazole, daptomycin, linezolid, and vancomycin).

Doripenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Facultative Gram-negative microorganisms
Acinetobacter baumannii
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa

Facultative Gram-positive microorganisms
Streptococcus constellatus
Streptococcus intermedius


Anaerobic microorganisms
Bacteroides caccae
Bacteroides fragilis
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Peptostreptococcus micros

At least 90 percent of the following microorganisms exhibit an in vitro minimal inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for doripenem of organisms of the same type shown in Table 6. The safety and efficacy of doripenem in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Facultative Gram-positive microorganisms
Staphylococcus aureus (methicillin-susceptible isolates only)
Streptococcus agalactiae
Streptococcus pyogenes

Facultative Gram-negative microorganisms
Citrobacter freundii
Enterobacter cloacae
Enterobacter aerogenes
Klebsiella oxytoca
Morganella morganii
Serratia marcescens

Pharmacodynamics------------------------------------
Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for doripenem has not been evaluated in patients.

In a randomized, positive- and placebo-controlled crossover QT study, 60 healthy subjects were administered DORIBAX® 500 mg IV every 8 hours x 4 doses and DORIBAX® 1g IV every 8 hours x 4 doses, placebo, and a single oral dose of positive control. At both the 500 mg and 1g DORIBAX® doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

Metabolism
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite (doripenem-M1) occurs primarily via dehydropeptidase-I. The mean (SD) plasma doripenem-M1-to-doripenem AUC ratio following single 500 mg and 1 g doses in healthy subjects is 18% (7.2%).

In pooled human liver microsomes, no in vitro metabolism of doripenem could be detected, indicating that doripenem is not a substrate for hepatic CYP450 enzymes.

Excretion
Doripenem is primarily eliminated unchanged by the kidneys. The mean plasma terminal elimination half-life of doripenem in healthy non-elderly adults is approximately 1 hour and mean (SD) plasma clearance is 15.9 (5.3) L/hour. Mean (SD) renal clearance is 10.8 (3.5) L/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and active tubular secretion. In healthy adults given a single 500 mg dose of DORIBAX®, a mean of 70% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of the total radioactivity was recovered in feces after one week.

INDICATIONS AND USAGE  top of page

INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORIBAX® and other antibacterial drugs, DORIBAX® should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Complicated Intra-Abdominal Infections
DORIBAX® (doripenem for injection) is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.

Complicated Urinary Tract Infections, Including Pyelonephritis
DORIBAX® (doripenem for injection) is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii.

CONTRAINDICATIONS top of page

CONTRAINDICATIONS
Patients with known serious hypersensitivity to doripenem or to other drugs in the same class or patients who have demonstrated anaphylactic reactions to beta-lactams

PRECAUTIONS top of page

WARNINGS AND PRECAUTIONS
--Serious hypersensitivity (anaphylactic) reactions have been reported with carbapenems and other beta-lactams
--It has been shown that co-administration of DORIBAX® with valproic acid reduces the serum concentration of valproic acid. Patients with seizure disorders controlled with valproic acid or sodium valproate will therefore be at an increased risk for breakthrough seizures.
--Clostridium difficile-associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs

DRUG INTERACTIONS
Interacting Drug---- Interaction
Valproic acid----- Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects
Probenecid---- Reduces renal clearance of doripenem, resulting in increased doripenem concentrations
Drugs metabolized by cytochrome P450 enzymes Doripenem neither inhibits nor induces major cytochrome P450 enzymes

USE IN SPECIFIC POPULATIONS
--Dosage adjustment is required in patients with moderately or severely impaired renal function.
--DORIBAX® has not been studied in pediatric patients.

ADVERSE REACTIONS top of page

ADVERSE REACTIONS

Most common adverse reactions (>/= 5%) are headache, nausea, diarrhea, rash and phlebitis.

To report SUSPECTED ADVERSE REACTIONS, contact Ortho-McNeil Pharmaceutical, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION  top of page

DOSAGE AND ADMINISTRATION

Recommended Dosage
The recommended dosage of DORIBAX® is 500 mg administered every 8 hours by intravenous infusion over one hour in patients geq18 years of age. The recommended dosage and administration by infection is described in Table 1:
Table 1: Dosage of DORIBAX® by Infection
Infection Dosage Frequency Infusion Time
(hours)
Duration
*Duration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated.
†Duration can be extended up to 14 days for patients with concurrent bacteremia.
Complicated intra-abdominal infection 500 mg every 8 hours 1 5–14 days*
Complicated UTI, including pyelonephritis 500 mg every 8 hours 1 10 days*†
 
Patients with Renal Impairment
Table 2: Dosage of DORIBAX® in Patients with Renal Impairment
Estimated CrCl (mL/min) Recommended Dosage Regimen of DORIBAX®
> 50 No dosage adjustment necessary
geq 30 to leq50 250 mg* administered intravenously (over 1 hour) every 8 hours
> 10 to < 30 250 mg* administered intravenously (over 1 hour) every 12 hours
*see Preparation of 250 mg DORIBAX® dose using the 250 mg vial  and Preparation of 250 mg DORIBAX® dose using the 500 mg vial
The following formula may be used to estimate CrCl. The serum creatinine used in the formula should represent a steady state of renal function.
Males: Creatinine clearance (mL/min) = weight (kg) × (140 - age in years)
72 × serum creatinine (mg/dL)
 
Females: Creatinine clearance (mL/min) = 0.85 × value calculated for males

DORIBAX® is hemodialyzable; however, there is insufficient information to make dose adjustment recommendations in patients on hemodialysis.

Preparation of Solutions
DORIBAX® does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparation of the infusion solution.

To prepare DORIBAX infusions in Baxter Minibag Plus™ infusion bags consult the infusion bag manufacturer's instructions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit. DORIBAX infusions range from clear, colorless solutions to solutions that are clear and slightly yellow. Variations in color within this range do not affect the potency of the product.

Preparation of 500 mg DORIBAX® dose using the 500 mg vial
--Constitute the 500 mg vial with 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension. The resultant concentration is approximately 50 mg/mL. CAUTION: THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION.
--Withdraw the suspension using a syringe with a 21 gauge needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose; gently shake until clear. The final infusion solution concentration is approximately 4.5 mg/mL.

Preparation of 250 mg DORIBAX® dose using the 250 mg vial
--Constitute the 250 mg vial with 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension. The resultant concentration is approximately 25 mg/mL. CAUTION: THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION.
--Withdraw the suspension using a syringe with a 21 gauge needle and add it to an infusion bag containing either 50 or 100 mL of normal saline or 5% dextrose; gently shake until clear. The final infusion solution concentration is approximately 4.2 mg/mL (50 mL infusion bag) or approximately 2.3 mg/mL (100 mL infusion bag).

Preparation of 250 mg DORIBAX® dose using the 500 mg vial
--Constitute the 500 mg vial with 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) and gently shake to form a suspension. The resultant concentration is approximately 50 mg/mL. CAUTION: THE CONSTITUTED SUSPENSION IS NOT FOR DIRECT INJECTION.
--Withdraw the suspension using a syringe with a 21 gauge needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose; gently shake until clear.
-- Remove 55 mL of this solution from the bag and discard.
--Infuse the remaining solution, which contains 250 mg (approximately 4.5 mg/mL).

Compatibility
The compatibility of DORIBAX® with other drugs has not been established. DORIBAX® should not be mixed with or physically added to solutions containing other drugs.

Storage of Constituted Solutions
Upon constitution with sterile water for injection or 0.9% sodium chloride (normal saline) injection, DORIBAX suspension in the vial may be held for 1-hour prior to transfer and dilution in the infusion bag.

Following dilution of the suspension with normal saline or 5% dextrose, DORIBAX infusions stored at room temperature or under refrigeration should be completed according to the times in Table 3.
Table 3: Storage and Stability Times of Infusion Solutions Prepared in Normal Saline or 5% Dextrose
Infusion prepared in Stability Time at Room Temp.
(includes room temperature storage and infusion time)
Stability time at 2–8°C (Refrigeration)
(includes refrigerator storage and infusion time)
Normal saline 12 hours 72 hours
5% Dextrose 4 hours 24 hours

Constituted DORIBAX suspension or DORIBAX infusion should not be frozen. This storage information applies also to DORIBAX® diluted in Baxter Minibag Plus™.

HOW SUPPLIED top of page

DOSAGE FORMS AND STRENGTHS
Single use clear glass vials containing 250 mg or 500 mg (on an anhydrous basis) of sterile doripenem powder.

REFERENCE

Package Insert data
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