Doribax

>10%

Headache (4-16%)

Nausea (4-12%)

Diarrhea (6-11%)

1-10%

Anemia (2-10%)

Phlebitis (4-8%)

Rash (1-5%)

Pruritus (3%)

Transaminases elevated (1-2%)

Oral candidiasis (1%)

Renal impairment/failure (1%)

Postmarketing Reports

Anaphylaxis

Leukopenia

Neutropenia

Seizure

Thrombocytopenia

Toxic epidermal necrolysis, Stevens-Johnson Syndrome

Interstitial pneumonia

Renal impairment/failure

Doribax is part of the drug class:

• Carbapenems

Distribution

Extent

Distributed into intra-abdominal tissues and fluids (e.g., retroperitoneal fluid,1 peritoneal exudate,1 11 bile,1 gallbladder tissue,1 urine).1

Not known if distributed into milk.1

Plasma Protein Binding

Approximately 8.1%.1

Elimination

Metabolism

Partially metabolized to an inactive ring-opened metabolite (doripenem M1) principally via dehydropeptidase-I.1

Not metabolized by CYP isoenzymes.1

Elimination Route

Excreted principally in urine as unchanged drug (70%).1

Half-life

Approximately 1 hour.1

Special Populations

Pharmacokinetics in patients with hepatic impairment not established.1

Removed by hemodialysis.1

AUC increased in patients with renal impairment.1

• It is used to treat bacterial infections.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Upset stomach.
• Loose stools (diarrhea).
• Irritation where Doribax is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Doribax, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Doribax (doripenem). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Doribax.

Review Date: October 4, 2017

1.1 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.

1.2 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.

1.3 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.

In the event of overdose, Doribax® should be discontinued and general supportive treatment given.

Doripenem can be removed by hemodialysis. In subjects with end-stage renal disease administered Doribax® 500 mg, the mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour hemodialysis session was 259 mg (52% of the dose). However, no information is available on the use of hemodialysis to treat overdosage. [see Clinical Pharmacology (12.3)]

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

12.1 Mechanism of Action

Doripenem is an antibacterial drug. [see Microbiology (12.4)]

12.2 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 × 4 doses and Doribax® 1 g IV every 8 hours × 4 doses, placebo, and a single oral dose of positive control. At both the 500 mg and 1 g Doribax® doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

12.3 Pharmacokinetics

• Plasma Concentrations

Mean plasma concentrations of doripenem following a single 1-hour intravenous infusion of a 500 mg dose of Doribax® to 24 healthy subjects are shown below in Figure 1. The mean (SD) plasma Cmax and AUC0–∞ values were 23.0 (6.6) µg/mL and 36.3 (8.8) µg•hr/mL, respectively.

Figure 1. Average Doripenem Plasma Concentrations Versus Time Following a Single 1-Hour Intravenous Infusion of Doribax® 500 mg in Healthy Subjects (N=24)

The pharmacokinetics of doripenem (Cmax and AUC) are linear over a dose range of 500 mg to 1 g when intravenously infused over 1 hour. There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or 1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function.

• Distribution

The average binding of doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The median (range) volume of distribution at steady state in healthy subjects is 16.8 L (8.09–55.5 L), similar to extracellular fluid volume (18.2 L).

Doripenem penetrates into several body fluids and tissues, including those at the site of infection for the approved indications. Doripenem concentrations in peritoneal and retroperitoneal fluid either match or exceed those required to inhibit most susceptible bacteria; however, the clinical relevance of this finding has not been established. Concentrations achieved in selected tissues and fluids following administration of Doribax® are shown in Table 5:

• 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 10.3 (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 71% 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.

• Special Populations

 Patients with Renal Impairment

Following a single 500 mg dose of Doribax®, the mean AUC of doripenem in subjects with mild (CrCl 50–79 mL/min), moderate (CrCl 31–50 mL/min), and severe renal impairment (CrCl ≤ 30 mL/min) was 1.6-, 2.8-, and 5.1-times that of age-matched healthy subjects with normal renal function (CrCl ≥ 80 mL/min), respectively. Dosage adjustment is necessary in patients with moderate and severe renal impairment. [see Dosage and Administration (2.2)]

A single 500 mg dose of Doribax® was administered to subjects with end stage renal disease (ESRD) either one hour prior to or one hour after hemodialysis (HD). The mean doripenem AUC following the post-HD infusion was 7.8-times that of healthy subjects with normal renal function. The mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour HD session was 231 mg and 28 mg, respectively, or a total of 259 mg (52% of the dose). There is insufficient information to make dose adjustment recommendations in patients on hemodialysis.

Patients with Hepatic Impairment

The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of doripenem are not expected to be affected by hepatic impairment.

Geriatric Patients

The impact of age on the pharmacokinetics of doripenem was evaluated in healthy male (n=6) and female (n=6) subjects ≥ 66 years of age. Mean doripenem AUC0-∞ was 49% higher in elderly adults relative to non-elderly adults. This difference in exposure was mainly attributed to age-related changes in creatinine clearance. No dosage adjustment is recommended for elderly patients with normal (for their age) renal function.

Gender

The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male (n=12) and female (n=12) subjects. Doripenem Cmax and AUC were similar between males and females. No dose adjustment is recommended based on gender.

Race

The effect of race on doripenem pharmacokinetics was examined using a population pharmacokinetic analysis of data from phase 1 and 2 studies. No significant difference in mean doripenem clearance was observed across race groups and therefore, no dosage adjustment is recommended based on race.

• Drug Interactions

Administration of Doribax® 500 mg every 8 hours x 4 doses to 23 healthy male subjects receiving valproic acid 500 mg every 12 hours for 7 days decreased the mean Cmax of valproic acid by 44.5% (from 86.1 mcg/mL to 47.8 mcg/mL) and the mean Cmin by 77.7% (from 55.7 mcg/mL to 12.4 mcg/mL) compared to administration of valproic acid alone. The mean AUC0-tau of valproic acid also decreased by 63%. Conversely, the Cmax of the VPA-g metabolite was increased by 62.6% (from 5.19 mcg/mL to 8.44 mcg/mL) and the mean AUC0-tau of VPA-g was increased by 50%. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid. [see Warnings and Precautions (5.4) and Drug Interactions (7.1)]

Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations. Probenecid increased doripenem AUC by 75% and prolonged the plasma elimination half-life by 53%. [see also Drug Interactions (7.2)]

In vitro studies in human liver microsomes and hepatocytes indicate that doripenem does not inhibit the major cytochrome P450 isoenzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A11). Therefore, Doribax® is not expected to inhibit the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

Doribax® is also not expected to have CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4/5, or UGT1A1 enzyme-inducing properties based on in vitro studies in cultured human hepatocytes.

12.4 Microbiology

• Mechanism of Action

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. [see Indications and Usage (1)]
      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

• Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (1,3) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of doripenem powder. The MIC values should be interpreted according to the criteria provided in Table 6.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure (2,3) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 µg of doripenem to test the susceptibility of microorganisms to doripenem. Results should be interpreted according to the criteria in Table 6.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doripenem as MICs should be determined by standardized test methods (4). The MIC values obtained should be interpreted according to the criteria in Table 6.

n/a = not applicable

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor the performance of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard doripenem powder should provide the MIC values provided in Table 8. For the diffusion techniques using a 10 µg doripenem disk, the criteria noted in Table 7 should be achieved.

n/a = not applicable

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.