Dorio

Doripenem.

Each vial contains doripenem monohydrate equivalent to 500 mg doripenem.

Pharmacology: Pharmacodynamics: Doripenem belongs to the carbapenem class of antimicrobials with in vitro antibacterial activity against aerobic and anaerobic, gram-positive and gram-negative bacteria. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivated multiple essential penicillin-binding proteins (PBPs), resulting in inhibition of cell wall synthesis with subsequent cell death. In Escherichia coli and Pseudomonas aeruginosa, doripenem binds to penicillin-binding protein 2, which is involved in the maintenance of cell shape, as well as to penicillin-binding protein 3 and 4.
Pharmacokinetics: Absorption: The pharmacokinetics of doripenem (maximal drug concentration (C_max) and area under the concentration-time curve (AUC)) are linear over a dose range of 500 mg to 1 g when IV infused over 1 hour. There is no accumulation of doripenem following multiple IV infusions of 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 protein is approximately 8.1% and is independent of plasma drug concentrations. The median volume of distribution at steady state in healthy adults is 16.8 L, similar to extracellular fluid volume (18.2 L).
Metabolism: Doripenem is partially metabolized to a microbiologically inactive ring-opened metabolite (doripenem-M1) primarily via dehydropeptidase-1. The mean plasma doripenem-M1 to doripenem AUC ratio following single 500 mg and 1 g doses in healthy subjects is 18%.
Excretion: Doripenem is primarily eliminated unchanged by the kidneys and undergoes both glomerular filtration and active tubular secretion. The mean plasma terminal elimination half-life of doripenem in healthy nonelderly adults is approximately 1 hour and mean plasma clearance is 15.9 L/h. Mean renal clearance is 10.8 L/h.

Complicated intra-abdominal infections: As a single agent for the treatment of complicated intra-abdominal infections caused by E. coli, Klebsiella pneumoniae, P. aeruginosa, Bacteroides cascae, B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, Streptococcus intermedius, S. constellatus and Peptostreptociccus micros.
Complicated urinary tract infections, including pyelonephritis: As a single agent for the treatment of complicated urinary tract infections (UTIs), including pyelonephritis caused by E. coli including cases with concurrent bacteremia, K. pneumoniae, Proteus mirabilis, P. aeruginosa and Acinetobacter baumannii.
Nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

DORIO is administered by IV infusion. (See Table 1.)

Click on icon to see table/diagram/image

Duration of therapy includes a possible switch to an appropriate oral therapy after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated. (See Table 2.)

Click on icon to see table/diagram/image

DORIO is removed by hemodialysis; data are insufficient to recommend dosage adjustment in patients undergoing hemodialysis.
Preparation for administration: Aseptic technique must be observed when preparing solutions of DORIO.
Reconstitute the vial with 10 mL of sterile water for injection or sodium chloride 0.9% injection (normal saline) and gently shake to form a suspension. The reconstituted suspension is not for direct injection. It is stable for up to 1 hour prior to transfer and dilution in the infusion bag.
Withdraw the suspension using a syringe with needle and add it to an infusion bag containing 100 mL of normal saline or 5% dextrose, gently shake until clear. (for 500 mg dose)
For 250 mg dose, remove 55 mL of this solution from the bag and discard. Infuse the remaining solution.
Following dilution, store at controlled room temperature or under refrigeration should be completed according to the times in the table: see Table 3.

Click on icon to see table/diagram/image

Reconstituted and diluted DORIO solutions should be inspected visually for particulate matter and discoloration. Final solutions range from clear and colorless to clear, slightly yellow solution. DORIO should not be admixed or added to solutions containing other drugs. It should not be frozen.

In the event of overdose, discontinue DORIO and give general supportive treatment. DORIO can be removed by hemodialysis. However, no information is available on the use of hemodialysis to treat overdosage.

Known serious hypersensitivity to doripenem or other drugs in the same class or in patients who have demonstrated anaphylactic reactions to β-lactams.

Sensitivity Reactions: Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) and serious skin reactions reported with β-lactams. Cross-allergenicity occurs among β-lactams antibiotics, including penicillins and cephalosporins. If an allergic reaction occurs, discontinue DORIO. Serious active hypersensitivity (anaphylactic) reactions require emergency treatment.
Clostridium difficile-associated Diarrhea and Colitis (CDAD): Treatment with DORIO alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile-associated diarrhea and colitis (also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives and may range in severity from mild diarrhea to fatal colitis. Consider in all patients who present with diarrhea following DORIO use, since CDAD has been reported to occur more than 2 months after administration of antibacterial agent.
Selection and Use of Anti-infectives: To reduce development of drug-resistant bacteria and maintain effectiveness of DORIO, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.
Pneumonitis with inhalational use: When doripenem has been used investigationally via inhalation, pneumonitis has occurred. Do not administration DORIO by this route.

Use in Pregnancy: Pregnancy Category B.
Use in Lactation: Not known whether DORIO is distributed into milk in humans. Caution is advised in nursing women.

Headache, nausea, diarrhea, rash, phlebitis, anemia, renal impairment/failure, pruritus, increased hepatic enzymes, oral candidiasis, and vulvomycotic infection.

Probenecid: Decreased renal tubular secretion of DORIO; increased plasma concentrations, increased AUC and prolonged half-life of DORIO. Concomitant use not recommended.
Valproic acid: DORIO may inhibit valproic acid glucoronide hydrolysis and reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Monitor serum valproic acid levels frequency after initiating DORIO therapy. Consider alternative anti-infective or anticonvulsant therapy if therapeutic serum valproic acid concentrations cannot be maintained or seizures occur.

Do not store above 30°C.

Other Beta-Lactams

J01DH04 - doripenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

S