Limited experience with 4-hr infusions of 1 g every 8 hr has shown this dosage to be well tolerated. Patients with renal impairment have not been studied at this dosage and should not receive this dose.

Renal Impairment: In patients whose creatinine clearance (CrCl) is >50 mL/min, no dosage adjustment is necessary. In patients with moderate renal impairment (CrCl greater than or equal to 30 to less than or equal to 50 mL/min), the dosage of Doribax should be 250 mg every 8 hr. In patients with severe renal impairment (CrCl >10 to <30 mL/min), the dosage of Doribax should be 250 mg every 12 hr.

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)

Hepatic Impairment: No dosage adjustment is necessary.

Age, Gender and Race: No dosage adjustment is recommended based on age (greater than or equal to 18 years), gender or race.

It is not known whether Doribax is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Doribax is administered to nursing women (see Animal Toxicology under Actions).

Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. It is not anticipated that Doribax will affect the ability to drive and use machines.

During clinical trials, adverse drug reactions that led to Doribax discontinuation were nausea (0.1%), diarrhea (0.1%), pruritus (0.1%), vulvomycotic infection (0.1%), hepatic enzyme increased (0.2%), and rash (0.2%).

Adverse Reaction Information from Spontaneous Reports: The adverse drug reactions identified during post-marketing experience with Doribax by frequency category estimated from spontaneous reporting rates are anaphylaxes (very rare).

Microbiology: Doripenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections (see Indications).

Gram-Positive Aerobes: Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus intermedius, Streptococcus constellatus, Staphylococcus aureus (methicillin-susceptible strains).

Gram-Negative Aerobes: Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli (including levofloxacin-resistant strains), Klebsiella pneumoniae, Haemophilus influenzae, Proteus mirabilis, Pseudomonas aeruginosa.

Anaerobes: Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides caccae, Bacteroides uniformis, Bacteroides vulgatus, Peptostreptococcus micros.

Other Bacteria: At least 90% of the following microorganisms exhibit an in vitro MIC less than or equal to the susceptible breakpoint for doripenem. However, the efficacy of doripenem in treating clinical infections due to these microorganisms has not been established.

Gram-Positive Aerobes: Enterococcus avium, Staphylococcus epidermidis (methicillin-susceptible strains only), Staphylococcus haemolyticus (methicillin-susceptible strains only), Staphylococcus saprophyticus, Staphylococcus agalactiae (including macrolide-resistant strains), Staphylococcus pneumoniae (penicillin-resistant or ceftriaxone-resistant strains), Staphylococcus pyogenes, Viridans group streptococci (penicillin-intermediate and penicillin-resistant strains).

Note: Staphylococci, which are resistant to methicillin/oxacillin should be considered resistant to doripenem.

Gram-Negative Aerobes: Acinetobacter calcoaceticus, Aeromonas hydrophila, Citrobacter diversus, Citrobacter freundii (including ceftazidime-resistant strains), Enterobacter aerogenes, Enterobacter cloacae (ceftazidime-resistant strains), Escherichia coli (ESBL producing strains), Haemophilus influenzae (b-lactamase producing strains or strains that are ampicillin-resistant, non-b-lactamase producing strains [BLNAR]), Klebsiella pneumoniae (ESBL producing strains), Klebsiella oxytoca, Morganella morganii, Proteus mirabilis (ESBL producing strains), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa (ceftazidime-resistant strains), Salmonella spp, Serratia marcescens (including ceftazidime-resistant strains), Shigella spp.

Anaerobes: Bacteroides ovatus, Bilophilora wadsworthia, Clostridium spp, Peptostreptococcus magnus, Porphyromonas spp, Prevotella spp, Suterella wadsworthia.

Susceptibility Testing: Susceptibility testing should be performed using standardized methods and the following breakpoints are to be utilized in the evaluation of bacterial sensitivity. (See Table 1.)

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Clinical Efficacy: Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia: A total of 969 patients with nosocomial pneumonia were randomized and treated in two phase 3 clinical studies.

In one study, 444 adults with clinically and radiologically documented nosocomial pneumonia, including ventilator-associated pneumonia (VAP) with onset within the first 5 days of ventilation (n=55), were randomized and treated in an international, multi-center, randomized, open-label study comparing doripenem (500 mg administered over 1 hr every 8 hr) to piperacillin/tazobactam (4.5 g every 6 hr). Both regimens allowed the option to switch to oral levofloxacin (750 mg once daily) after a minimum of 3 days of IV therapy for a total of 7-14 days of IV and oral treatment. Overall, adjunctive anti-pseudomonal therapy was started in 81% of clinically evaluable patients.

In a second study, 525 adults with clinically and radiologically documented ventilator-associated pneumonia (61% of clinically evaluable patients had late onset VAP [mechanical ventilation for greater than or equal to 5 days]) were randomized and treated in an international, multi-center, randomized, open-label study comparing doripenem (500 mg administered over 4 hr every 8 hr) to imipenem/cilastatin (500 mg to 1 g every 6 or 8 hr). Overall, adjunctive anti-pseudomonal therapy was started in 22% of clinically evaluable patients.

Doripenem was non-inferior to piperacillin/tazobactam and imipenem/cilastatin with regard to the clinical cure rates in clinically evaluable (CE) and in clinical modified intent-to-treat (cMITT) patients, ie in patients meeting the minimal definition for pneumonia at the test of cure (TOC) visit, 6-20 days after completing therapy. Clinical cure rates at TOC for both trials are displayed in Table 2.

Microbiological cure rates at TOC by pathogen in microbiologically evaluable (ME) patients are presented in Table 3. In the study of ventilator-associated pneumonia, in P. aeruginosa infections, the clinical cure rates were 80% (16/20) in patients treated with Doribax compared with 43% (6/14) imipenem treated patients. (See Table 3.)

Complicated Intra-Abdominal Infections: A total of 946 adults with complicated intra-abdominal infections were randomized and received study medications in 2 identical multinational, multi-center, double-blind studies comparing Doribax (500 mg administered over 1 hr every 8 hr) to meropenem (1 g administered over 3-5 minutes every 8 hr). Both regimens allowed the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg twice daily) after a minimum of 3 days of IV therapy for a total of 5-14 days of IV and oral treatment. Patients with complicated appendicitis, or other complicated intra-abdominal infections, including bowel perforation, cholecystitis, intra-abdominal or solid organ abscess and generalized peritonitis were enrolled.

Doribax was non-inferior to meropenem with regard to clinical cure rates in microbiologically evaluable (ME) patients, ie in patients with susceptible pathogens isolated at baseline and no major protocol deviations at test of cure (TOC) visit, 21-60 days after completing therapy. Doribax was also non-inferior to meropenem in microbiological modified intent-to-treat (mMITT) patients, ie patients with baseline pathogens isolated regardless of susceptibility. Clinical cure rates at TOC are displayed by patient populations in Table 4. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 5.(See Tables 4 and 5.)

Complicated Urinary Tract Infections, Including Complicated and Uncomplicated Pyelonephritis: A total of 1171 adults with complicated urinary tract infections, including pyelonephritis (49% of microbiologically evaluable patients) were randomized and received study medications in 2 multi-center, multinational studies. Complicated pyelonephritis, ie pyelonephritis associated with predisposing anatomical or functional abnormality, comprised 17% of patients with pyelonephritis. One study was double-blind and compared Doribax (500 mg administered over 1 hr every 8 hr) to IV levofloxacin (250 mg every 24 hr). The second study was a non-comparative study but of otherwise similar design. Both studies permitted the option of switching to oral levofloxacin (250 mg every 24 hr) after a minimum of 3 days of IV therapy for a total of 10 days of treatment. Patients with confirmed concurrent bacteremia were allowed to receive 500 mg of IV levofloxacin (either IV or oral as appropriate) for a total of 10-14 days of treatment.

Doribax was non-inferior to Ievofloxacin with regard to the microbiological cure rates in microbiologically evaluable (ME) patients, ie patients with baseline uropathogens isolated, no major protocol deviations and urine cultures at test of cure (TOC) visit 5-11 days after completing therapy. Doribax was also non-inferior to levofloxacin in microbiological modified intent-to-treat, (mMITT) patients, ie patients with pretreatment urine cultures. Overall microbiological and clinical cure rates at TOC are displayed in Table 6. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 7. In patients with pyelonephritis, the microbiological cure rate was 223/253 (92%) with Doribax and in complicated pyelonephritis the cure rate was 34/40 (85%). (See Tables 6 and 7)

Pharmacokinetics: Plasma Concentrations: Average plasma concentrations (mcg/mL) of doripenem following single 1-hr and 4-hr IV infusions of a 500 mg dose and a single 4-hr infusion of a 1 g dose are presented in Table 8.

The pharmacokinetics of doripenem (Cmax and AUC) is linear over a dose range of 500 mg to 1 g when intravenously infused over either 1 or 4 hr. There is no accumulation of doripenem following multiple IV infusions of either 500 mg or 1 g administered every 8 hr for 7-10 days in patients with normal renal function.

Distribution: The average binding of doripenem to plasma proteins was approximately 8.1% and is independent of plasma drug concentrations. The volume of distribution at steady state is approximately 16.8 L, similar to extracellular fluid volume (18.2 L) in man. Doripenem penetrates well into several body fluids and tissue, eg uterine tissue, retroperitoneal fluid, prostatic tissue, gallbladder tissue and urine, achieving concentrations in excess of those required to inhibit most bacteria.

Metabolism: Metabolism of doripenem to a microbiologically inactive ring-opened metabolite occurs primarily via dehydropeptidase-1. No in vitro metabolism of doripenem could be detected, CYP450-mediated or otherwise, in the presence or absence of NADPH.

Elimination: Doripenem is primarily eliminated unchanged by the kidneys. Mean plasma terminal elimination half-life of doripenem in healthy young adults is approximately 1-hr and plasma clearance is approximately 15.9 L/hr. Mean renal clearance is 10.3 L/hr. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem seen with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and tubular secretion. In healthy young adults, given a single 500 mg dose of Doribax, 71% and 15% of the dose was recovered in urine as unchanged drug and ring-opened metabolite, respectively. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy young adults, <1% of the total radioactivity was recovered in feces.

Special Populations: Patients with Renal Impairment: Following a single 500 mg dose of Doribax, AUC increased 1.6-fold, 2.8-fold, and 5.1-fold in subjects with mild (CrCI 51-79 mL/min), moderate (CrCI 31-50 mL/min), and severe renal insufficiency (CrCl less than or equal to 30 mL/min), respectively, compared to age-matched healthy subjects with normal renal function (CrCl greater than or equal to 80 mL/min). PK simulations also were performed in patients with varying degrees of renal dysfunction to determine doses that would achieve target attainment rates (%T>MIC) and exposures (AUC) similar to those in subjects with normal renal function. Dosage adjustment is necessary in patients with moderate and severe renal impairment. (See Renal Impairment under Dosage & Administration.)

Patients with Hepatic Impairment: The pharmacokinetics of doripenem in patients with hepatic impairment has not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of Doribax is not expected to be affected by hepatic impairment. (See Patients with Hepatic Impairment under Dosage & Administration.)

Geriatric Patients: The impact of age on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects greater than or equal to 66 years. Doripenem AUC increased 49% in elderly adults relative to young adults. These changes were 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 or gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem AUC was 15% higher in females compared to males. No dose adjustment is recommended based on gender.

Race: The effect of race on doripenem pharmacokinetics was examined through a population pharmacokinetic analysis. A 29% increase in mean doripenem clearance was observed in Hispanic/Latino subjects whereas no change in clearance was observed for African Americans. Although there were a limited number of subjects, mean doripenem clearance in Asians appeared to be similar to that in Caucasians. No dosage adjustment is recommended in Hispanic/Latino patients.

Drug Interactions: Probenecid competes with doripenem for active tubular secretion and thus reduces the renal clearance of doripenem. Probenecid increased doripenem AUC by 75% and plasma half-life by 53%.

In vitro studies in human liver microsomes and hepatocytes indicate that doripenem does not inhibit the major cytochrome P450 isoenzymes. Therefore, Doribax is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.

Doribax also is not expected to have enzyme-inducing properties based on in vitro studies in cultured human hepatocytes. (See also Interactions.)

Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Because of the short duration of treatment and intermittent clinical use, long-term carcinogenicity studies have not been conducted with doripenem.

Doripenem did not show evidence of mutagenic activity in standard tests that included bacterial reverse mutation assay, chromosomal aberration assay with chinese hamster lung fibroblast cells, and mouse bone marrow micronucleus assay.

IV injection of doripenem had no adverse effects on general fertility of treated male and female rats or on postnatal development and reproductive performance of the offspring at doses as high as 1g/kg/day (based on AUC, at least equal to the exposure to humans at the dose of 500 mg every 8 hr).

Animal Toxicology and Pharmacology: IV administration of doripenem to rats during late gestation and lactation at doses as high as 1 g/kg/day (based on AUC, at least equal to the exposure to humans at the dose of 500 mg every 8 hr) produced no adverse effects. The clinical significance of this observation is unknown.

There is no clinical experience on the administration of Doribax during labor and delivery.

Central GABA receptor binding inhibition, associated with convulsion-inducing effects of b-Iactams as determined in mouse brain synaptic membranes required at least 10-fold the concentration for doripenem than for imipenem, panipenem, and cefazolin. Following direct administration into the lateral ventricle of mice, doripenem did not produce convulsions at doses at least 10-fold greater than convulsion-producing doses of imipenem, panipenem and cefazolin. Likewise, data suggest that doripenem has weaker convulsion inducing effects than imipenem or meropenem when administered by intraventricular or IV injection to dogs and rats implanted with EEG electrodes.

Teratogenicity: Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight following IV administration during organogenesis at doses as high as 1000 mg/kg/day in rats and 50 mg/kg/day in rabbits (based on AUC, at least 2.7 and 0.9 times the exposure to humans dosed at 500 mg every 8 hr, respectively).