Doribax

Doribax

doripenem

Manufacturer:

Celltrion Healthcare

Distributor:

DKSH
Full Prescribing Info
Contents
Doripenem.
Description
Doribax, doripenem monohydrate contains doripenem 500 mg on an anhydrous basis. All references to doripenem activity are expressed in terms of the active doripenem moiety. Doribax is not formulated with any inactive ingredients. The powder is constituted for IV infusion. The pH of the infusion solution is between 4.5 to 5.5.
Action
Pharmacotherapeutic Group: Carbapenems. ATC Code: J01DH04.
Pharmacology: Doripenem is a broad-spectrum carbapenem with potent in vitro antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria. It is generally 2- to 4-fold more potent against P. aeruginosa compared to imipenem or meropenem (see Microbiology).
Pharmacodynamics: Mechanism of Action: Doripenem is a carbapenem β-lactam antibiotic. It exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. It inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death.
Doripenem is stable to hydrolysis by most β-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolyzing β-lactamases. In vitro selection for resistant strains of Pseudomonas aeruginosa at a concentration 4 times the minimum inhibitory concentration (MIC) occurred at a frequency of <2x10-9 for 7 of 8 strains exposed to doripenem, which was less frequent than for ertapenem, imipenem, meropenem, carbenicillin, ceftazidime, ciprofloxacin and tobramycin. Although cross-resistance may occur, some strains resistant to other carbapenems may be susceptible to doripenem.
In vitro synergy tests with doripenem show doripenem has little potential to antagonize or be antagonized by other antibiotics. Additivity or weak synergy with amikacin and levofloxacin has been seen for P. aeruginosa and for gram-positives with daptomycin, linezolid, levofloxacin and vancomycin.
Pharmacodynamic Effects: Similar to other β-lactam antimicrobial agents, the time that the plasma concentration of doripenem exceeds the MIC (T>MIC) of the infecting organism has been shown to best correlate with efficacy in preclinical pharmacokinetic/pharmacodynamic studies. Extending the infusion time to 4 hrs maximizes the T>MIC for a given dose and is the basis for the recommendation to administer 4-hr infusions in patients with nosocomial pneumonia including ventilator-associated pneumonia at risk for infections due to less susceptible pathogens. (See Dosage & Administration.)
Pharmacokinetics: Plasma Concentrations: Average plasma concentrations (mcg/mL) of doripenem following single 1- 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 1. (See Table 1.)

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There is no accumulation of doripenem following multiple IV infusions of either 500 mg or 1 g administered every 8 hrs for 7-10 days in subjects with normal renal function. The pharmacokinetics of doripenem are linear over a dose range of 500 mg to 2 g when IV infused over 1 hr and 500 mg to 1 g when IV infused over 4 hrs.
Doripenem single-dose pharmacokinetics (after a 4-hr infusion) in adults with cystic fibrosis are consistent with those in adults without cystic fibrosis. Adequate and well-controlled studies to establish the safety and efficacy of doripenem in patients with cystic fibrosis have not been conducted.
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 tissues 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 nicotinamide adenine dinucleotide phosphate (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-, 2.8- and 5.1-fold in subjects with mild [creatinine clearance (CrCl) 51-79 mL/min], moderate (CrCl 31-50 mL/min) and severe renal insufficiency (CrCl ≤30 mL/min), respectively, compared to age-matched healthy subjects with normal renal function (CrCl ≥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 Patients with 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 ≥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 of gender on the pharmacokinetics of doripenem was evaluated in healthy male and female subjects. Doripenem AUC was 13% 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. No significant difference in mean doripenem clearance was observed across race groups and therefore, no dosage adjustment is recommended for race.
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 P-450 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.
Following co-administration of doripenem and valproic acid, the serum concentrations of valproic acid were rapidly reduced (AUC was reduced by 63%). This is consistent with case reports for other carbapenems, where serum concentrations of valproic acid were reduced upon co-administration with a carbapenem. The interaction resulted in valproic acid levels falling below the therapeutic range in healthy subjects. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid. (See also Interactions.)
Toxicology: Preclinical Safety Data: 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 administered every 8 hrs) 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 β-lactams 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 electroencephalogram (EEG) electrodes.
Carcinogenicity, Mutagenicity & 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 1 g/kg/day (based on AUC, at least equal to the exposure to humans at the dose of 500 mg administered every 8 hrs).
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: Staphylococcus epidermidis (methicillin-susceptible strains only), Staphylococcus haemolyticus (methicillin-susceptible strains only), Staphylococcus saprophyticus, Streptococcus agalactiae (including macrolide-resistant strains), Streptococcus pneumoniae (penicillin- or ceftriaxone-resistant strains), Streptococcus 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-nonsusceptible strains), Enterobacter aerogenes, Enterobacter cloacae (ceftazidime-nonsusceptible strains), Escherichia coli [extended spectrum β-lactamase (ESBL)-producing strains], Haemophilus influenzae [β-lactamase-producing strains or strains that are ampicillin-resistant, non-β-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-nonsusceptible strains), Shigella spp.
Anaerobes: Bacteroides ovatus, Bilophila 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 2.

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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 (NP), Including Ventilator-Associated Pneumonia: A total of 969 patients with NP were randomized and treated in 2 phase 3 clinical studies.
In 1 study, 444 adults with clinically and radiologically documented NP, including ventilator-associated pneumonia (VAP) with onset within the first 5 days of ventilation (n=55 in clinically evaluable patients), were randomized and treated in an international, multicenter, open-label study comparing doripenem (500 mg administered over 1 hr every 8 hrs) to piperacillin/tazobactam (4.5 g administered every 6 hrs). Both regimens allowed the option to switch to oral levofloxacin (750 mg administered 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 antipseudomonal therapy was started in 81% of clinically evaluable patients.
In a 2nd study, 525 adults with clinically and radiologically documented ventilator-associated pneumonia [61% of clinically evaluable patients had late onset VAP (mechanical ventilation for ≥5 days)] were randomized and treated in an international, multicenter, open-label study comparing doripenem (500 mg administered over 4 hrs every 8 hrs) to imipenem/cilastatin (500 mg administered every 6 hrs or 1 g administered every 8 hrs). Overall, adjunctive antipseudomonal 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 3. (See Table 3.)

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Microbiological cure rates at TOC by pathogen in microbiologically evaluable (ME) patients are presented in Table 4. (See Table 4.) In the study of ventilator-associated pneumonia, in P. aeruginosa infections, the clinical cure rates were 65% (13/20) in patients treated with Doribax compared with 36% (5/14) in imipenem-treated patients.

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Complicated Intra-Abdominal Infections (cIAI): A total of 946 adults with cIAI were randomized and received study medications in 2 identical multinational, multicenter, double-blind studies comparing Doribax (500 mg administered over 1 hr every 8 hrs) to meropenem (1 g administered over 3-5 min every 8 hrs). Both regimens allowed the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg administered 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 cIAI, 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 ME patients ie, in patients with susceptible pathogens isolated at baseline and no major protocol deviations at 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 6.(See Tables 5 and 6.)

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Complicated Urinary Tract Infections (cUTI), Including Complicated and Uncomplicated Pyelonephritis: A total of 1171 adults with cUTI, including pyelonephritis (49% of ME patients) were randomized and received study medications in 2 multicenter, 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 hrs) to IV levofloxacin (250 mg administered every 24 hrs). The 2nd study was a noncomparative study but of otherwise similar design. Both studies permitted the option of switching to oral levofloxacin (250 mg administered every 24 hrs) 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 levofloxacin 500 mg IV (either IV or oral as appropriate) for a total of 10-14 days of treatment.
Doribax was non-inferior to levofloxacin with regard to the microbiological cure rates in ME patients ie, patients with uropathogens isolated from study-qualifying baseline urine cultures, no major protocol deviations and who had results from urine cultures obtained at the TOC visit 5-11 days after completing therapy. Doribax was also non-inferior to levofloxacin in mMITT patients ie, patients with study-qualifying pre-treatment urine cultures. Overall, microbiological and clinical cure rates at TOC are displayed in Table 7. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 8. In patients with pyelonephritis, the microbiological cure rate was 232/253 (92%) with Doribax and in complicated pyelonephritis, the cure rate was 34/40 (85%). (See Tables 7 and 8.)

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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 administered every 8 hrs, respectively).
Indications/Uses
As a single agent for the treatment of the following infections caused by susceptible bacteria (see Microbiology under Actions): Nosocomial pneumonia, including ventilator-associated pneumonia; complicated intra-abdominal infections; complicated urinary tract infections, including complicated and uncomplicated pyelonephritis and cases with concurrent bacteremia.
Because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic bacteria, Doribax can be considered for treatment of complicated and mixed infections. Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify causative organisms and to determine their susceptibility to doripenem. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage/Direction for Use
Recommended Dose: 500 mg administered every 8 hrs by IV infusion. The recommended dosage and administration by infection is described in Table 9. (See Table 9.)

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Limited experience with 4-hr infusions of 1 g administered every 8 hrs 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.
Patients with Renal Impairment: In patients whose CrCl is >50 mL/min, no dosage adjustment is necessary. In patients with moderate renal impairment (CrCl ≥30 to ≤50 mL/min), the dosage of Doribax should be 250 mg administered every 8 hrs. In patients with severe renal impairment (CrCl >10 to <30 mL/min), the dosage of Doribax should be 250 mg administered every 12 hrs. (See Instructions for Use and Handling: Preparation of Doribax 250 mg dose using the 500 mg vial under Cautions for Usage.)
The following formula may be used to estimate CrCl. The serum creatinine used in the formula should represent a steady state of renal function. (See equation.)

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Patients on Hemodialysis: Doribax is hemodialyzable; however, there is insufficient information to make dose adjustment recommendations in patients on hemodialysis.
Patients with Hepatic Impairment: No dosage adjustment is necessary.
Age, Gender and Race: No dosage adjustment is recommended based on age (≥18 years), gender or race.
Overdosage
In a phase 1 study in healthy subjects receiving doripenem 2 g infused over 1 hr every 8 hrs for 10-14 days, the incidence of rash was very common (5 of 8 subjects). The papuloerythermatous rash resolved within 10 days after doripenem administration was discontinued.
In the event of overdose, Doribax should be discontinued and general supportive treatment given until renal elimination takes place.
Doribax can be removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.
Contraindications
Patients with known serious hypersensitivity to doripenem or to other drugs in the same class or patients who have demonstrated anaphylactic reactions to β-lactams.
Special Precautions
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactam antibiotics. (See Contraindications.) These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with Doribax is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillins or other allergens. If Doribax is to be given to a penicillin- or other β-lactam-allergic patient, caution should be exercised because cross-hyperreactivity among β-lactam antibiotics has been clearly documented. If an allergic reaction to Doribax occurs, discontinue the drug. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment.
Pseudomembranous Colitis: Pseudomembranous colitis due to C. difficile has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who have received Doribax and who present with diarrhea.
Overgrowth of Nonsusceptible Bacteria: Prescribing Doribax in the absence of a proven or strongly suspected bacterial infection or for a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Pneumonitis with Inhalational Use: When used investigationally via inhalation, pneumonitis has occurred. Doribax should not be administered by this route.
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.
Use in pregnancy: Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight in preclinical studies (see Teratogenicity under Actions). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Doribax should be used during pregnancy only if clearly needed.
Use in lactation: 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 a nursing woman (see Toxicology: Animal Toxicology and Pharmacology under Actions).
Use In Pregnancy & Lactation
Use in pregnancy: Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight in preclinical studies (see Teratogenicity under Actions). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Doribax should be used during pregnancy only if clearly needed.
Use in lactation: 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 a nursing woman (see Toxicology: Animal Toxicology and Pharmacology under Actions).
Adverse Reactions
Adverse Effects from Clinical Trials: In 1338 adult patients who received Doribax in phase 3 clinical trials (500 mg administered every 8 hrs), adverse drug reactions occurring at a rate ≥1% in any indication (cUTI, cIAI and NP) are listed in Table 10. (See Table 10.)
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%), increased hepatic enzyme (0.2%) and rash (0.2%).

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In 1817 adult patients who received Doribax in phase 2 and 3 clinical trials (500 mg administered every 8 hrs), adverse reactions that were observed are listed in Table 11. (See Table 11.)
Adverse reactions that led to Doribax discontinuation were nausea (0.1%), diarrhea (0.1%), pruritus (0.1%), vulvomycotic infection (0.1%), increased hepatic enzyme (0.2%) and rash (0.2%).

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Adverse Drug Reactions Observed in <1% of Doribax-Treated Patients in Phase 2 and 3 Clinical Trials: Gastrointestinal Disorders: C. difficile colitis.
Immune System Disorders: Hypersensitivity.
Adverse Reaction Information from Spontaneous Reports: The following adverse reactions have been identified during post-approval use of Doribax:
Adverse Drug Reactions Identified During Post-Marketing Experience with Doribax by Frequency Category Estimated from Spontaneous Reporting Rates: Blood and the Lymphatic System Disorders: Very Rare: Thrombocytopenia, neutropenia.
Immune System Disorders: Very Rare: Anaphylaxis.
Skin and Subcutaneous Tissue Disorders: Very Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome.
Adverse Drug Reactions Identified During Post-Marketing Experience with Doribax by Frequency Category Estimated from Clinical Trials or Epidemiology Studies: Blood and the Lymphatic System Disorders: Uncommon: Thrombocytopenia, neutropenia.
Immune System Disorders: Frequency Not Known*: Anaphylaxis.
Skin and Subcutaneous Tissue Disorders: Frequency Not Known*: Toxic epidermal necrolysis, Stevens-Johnson syndrome.
*Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.
Drug Interactions
Probenecid: Probenecid competes with doripenem for active tubular secretion and thus, reduces the renal clearance of doripenem. Co-administration of probenecid with Doribax is not recommended.
Valproic Acid: Doripenem reduced serum valproic acid concentrations to subtherapeutic levels in healthy subjects (see Pharmacokinetics: Drug Interactions under Actions). Therefore, valproic acid concentrations in the blood should be monitored if Doribax is administered concomitantly with valproic acid or sodium valproate and alternative therapies should be considered.
Incompatibilities: 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.
Caution For Usage
Instructions for Use and Handling: 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 Doribax.
Preparation of Doribax 500- and 250-mg Dose Using the 500 mg Vial: 500-mg Dose: Add 10 mL of sterile water for injection or 0.9% sodium chloride injection (normal saline) to the 500 mg vial and gently shake to form a suspension. Inspect the suspension visually for foreign matter. (Note: The suspension is not for direct infusion.) Withdraw the suspension using a syringe and needle, and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose; gently shake until clear.
For the 250-mg dose, remove 55 mL of this solution from the bag and discard. Infuse all of this or the remaining solution to administer a 500- or 250-mg dose of doripenem, respectively.
Storage
Do not store above 30°C.
Shelf-Life: Reconstituted Suspension: Upon reconstitution with sterile water for injection or 0.9% sodium chloride (normal saline) injection, Doribax suspension in the vial may be held for 1 hr prior to transfer and dilution in the infusion bag.
Infusion Solution: Aseptic technique must be followed in preparation of the infusion solution.
Following dilution with normal saline or 5% dextrose, Doribax infusion stored at room temperature or under refrigeration should be completed according to the times in Table 12. (See Table 12.)

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MIMS Class
ATC Classification
J01DH04 - doripenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.
Presentation/Packing
Vial 500 mg (white to slightly yellowish off-white crystalline powd) x 10's.
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