Doribax

Generic Name: Doripenem
Class: Carbapenems
Chemical Name: (4R,5S,6S)-3-[((3S,5S)-5-[[(aminosulfonyl)amino] methyl]-3-pyrrolidinyl)thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid monohydrate.
Molecular Formula: C15H24N4O6S2
CAS Number: 148016-81-3

Introduction

Antibacterial; carbapenem β-lactam antibiotic.1 3

Uses for Doribax

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by susceptible Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. caccae, B. thetaiotaomicron, B. uniformis, B. vulgatus, Streptococcus intermedius, S. constellatus, or Peptostreptococcus micros.1 2 10

Slideshow: 10 Things to Know About Antibiotic Resistance

Urinary Tract Infections

Treatment of complicated urinary tract infections (including pyelonephritis) caused by susceptible E. coli (including cases with concurrent bacteremia) or susceptible K. pneumoniae, Proteus mirabilis, Ps. aeruginosa, or Acinetobacter baumannii.1 10

Respiratory Tract Infections

Has been used for treatment of bronchopulmonary infection in patients with cystic fibrosis who are colonized with Ps. aeruginosa or Burkholderia cepacia (designated an orphan drug by FDA for this use).16

Has been used for treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP).6 13 14

Doribax Dosage and Administration

Administration

Administer by IV infusion.1

Not for administration via inhalation.1 (See Pneumonitis under Cautions.)

For solution and drug compatibility information, see Compatibility under Stability.

IV Administration

Reconstitution

Use strict aseptic technique since drug product contains no preservative.1

Reconstitute vial containing 500 mg of doripenem with 10 mL of sterile water for injection or 0.9% sodium chloride injection; shake gently to provide a suspension containing 50 mg/mL.1

Reconstituted suspension is not for direct injection; must be further diluted in ≤1 hour following reconstitution.1 (See Storage under Stability.)

Dilution

For a 500-mg dose, withdraw contents of the reconstituted vial with a 21-gauge needle and add it to an infusion bag containing 100 mL of 0.9% sodium chloride injection or 5% dextrose for injection to provide a solution containing 500 mg (4.5 mg/mL); gently shake until clear.1

For a 250-mg dose, withdraw contents of the reconstituted vial with a 21-gauge needle and add it to an infusion bag containing 100 mL of 0.9% sodium chloride injection or 5% dextrose for injection; gently shake until clear.1 Remove and discard 55 mL of the solution from the bag to provide a solution containing 250 mg (4.5 mg/mL).1

Rate of Administration

Administer by IV infusion over 1 hour.1

Dosage

Available as doripenem monohydrate; dosage expressed in terms of doripenem.1

Adults

Intra-abdominal Infections
IV

500 mg every 8 hours.1 Usual duration is 5–14 days; treatment may be switched to an appropriate oral anti-infective after ≥3 days, if clinical improvement has been demonstrated.1

Urinary Tract Infections
IV

500 mg every 8 hours.1 Usual duration is 10 days but may be extended up to 14 days for patients with concurrent bacteremia; treatment may be switched to an appropriate oral anti-infective after ≥3 days, if clinical improvement has been demonstrated.1

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

Dosage adjustment recommended in patients with Clcr ≤50 mL/minute.1

Dosage for Adults with Renal Impairment1

Clcr (mL/minute)

Daily Dosage

30–50

250 mg every 8 hours

11–29

250 mg every 12 hours

Insufficient data to recommend dosage adjustments in patients undergoing hemodialysis.1

Geriatric Patients

No dosage adjustments except those related to renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Doribax

Contraindications

  • Known hypersensitivity to doripenem or other carbapenems.1

  • History of anaphylactic reaction to β-lactams.1

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives may permit overgrowth of Clostridium difficile.1 19 20 21 22 23 C. difficile-associated diarrhea and colitis (CDAD; 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.1

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 19 20 21 22 23 Obtain a careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, the anti-infective may need to be discontinued.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin); and surgical evaluation when clinically indicated.1 19 20 21 22 23

Selection and Use of Anti-infectives

Use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1

Use results of culture and in vitro susceptibility testing.1 If such data are unavailable, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

Pneumonitis

Pneumonitis reported following administration by inhalation;1 not for inhalation administration.1

Interaction with Valproic Acid

Doripenem reduces valproic acid serum concentrations to subtherapeutic concentrations; possible increased risk of seizures.a Monitor serum valproic acid concentrations and consider alternative therapies.a (See Specific Drugs under Interactions.)

Sensitivity Reactions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) and serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) reported.1

If hypersensitivity occurs, discontinue doripenem and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, IV fluids, IV antihistamines, pressor amines, oxygen and maintenance of an adequate airway).1

Cross-hypersensitivity

Cross-allergenicity occurs among β-lactam antibiotics, including penicillins, cephalosporins, and other β-lactams.1

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to doripenem, cephalosporins, penicillins, or other drugs.1

General Precautions

CNS Effects

Seizures and other CNS effects (e.g., confusional states, myoclonic activity) reported with carbapenems (e.g., ertapenem, imipenem, meropenem), especially in those with underlying CNS disorders (e.g., brain lesions, history of seizures) and/or compromised renal function.8 10 24 25 26

Rarely, seizures reported in patients receiving doripenem;1 causality not established.1

Specific Populations

Pregnancy

Category B.1

Lactation

Not known if doripenem is distributed into milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.1

Substantially eliminated by kidneys; risk of adverse reactions may be greater in geriatric patients with impaired renal function or prerenal azotemia.1 Select dosage with caution and assess renal function periodically since geriatric patients are more likely to have renal impairment.1

Hepatic Impairment

Pharmacokinetics not established but impact of hepatic impairment should be minimal.1

Renal Impairment

Increased AUC.1 Dosage adjustments and monitoring of renal function recommended in patients with moderate or severe renal impairment (Clcr ≤50 mL/minute).1 (See Special Populations under Dosage and Administration.)

Risk of adverse reactions may be greater in patients with impaired renal function.1

Common Adverse Effects

Headache, nausea, diarrhea, rash, phlebitis.1

Interactions for Doribax

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A11.1 Not expected to induce CYP1A2, 2B6, 2C9, 2C19, or 3A4/5.1 Pharmacokinetic interactions unlikely with drugs metabolized by these isoenzymes.1

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT) 1A1

Not expected to induce UGT 1A1;1 pharmacokinetic interactions unlikely with drugs metabolized by this enzyme.1

Specific Drugs

Drug

Interaction

Comments

Anti-infective agents (e.g., amikacin, co-trimoxazole, daptomycin, levofloxacin, linezolid, vancomycin)

Minimal potential to antagonize or be antagonized by other anti-infectives1 10

Probenecid

Decreased renal tubular secretion of doripenem; increased doripenem concentrations, AUC, and prolonged half-life1

Concomitant use not recommended1

Valproic acid

Concomitant administration decreases valproic acid to subtherapeutic concentrations; AUC reduced by 63% a

Pharmacokinetics of doripenem unaffecteda

Monitor serum valproic acid concentrations if administered concomitantly;a consider alternative anti-infective or anticonvulsant therapya

Doribax Pharmacokinetics

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 doripenem is 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

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).1

Reconstituted suspension containing 50 mg/mL, in sterile water for injection or 0.9% sodium chloride injection, is stable for ≤1 hour; do not freeze.1

Diluted IV solutions prepared using 0.9% sodium chloride injection or 5% dextrose for injection are stable for 8 or 4 hours, respectively, at room temperature (including infusion time) or 24 hours at 2–8°C (including infusion time); do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Y-site CompatibilityHID

Compatible

Acyclovir sodium

Amikacin sulfate

Aminophylline

Amiodarone HCl

Anidulafungin

Atropine sulfate

Azithromycin

Bumetanide

Calcium gluconate

Carboplatin

Caspofungin acetate

Ceftaroline fosamil

Ciprofloxacin

Cisplatin

Cyclophosphamide

Cyclosporine

Daptomycin

Dexamethasone sodium phosphate

Digoxin

Diltiazem HCl

Diphenhydramine HCl

Dobutamine HCl

Docetaxel

Dopamine HCl

Doxorubicin HCl

Enalaprilat

Esmolol HCl

Esomeprazole sodium

Etoposide phosphate

Famotidine

Fentanyl citrate

Fluconazole

Fluorouracil

Foscarnet sodium

Furosemide

Gemcitabine HCl

Granisetron HCl

Heparin sodium

Hydrocortisone sodium succinate

Hydromorphone HCl

Ifosfamide

Insulin, regular

Labetalol HCl

Levofloxacin

Linezolid

Lorazepam

Magnesium sulfate

Mannitol

Meperidine HCl

Methotrexate sodium

Methylprednisolone sodium succinate

Metoclopramide HCl

Metronidazole

Micafungin sodium

Midazolam HCl

Milrinone lactate

Morphine sulfate

Moxifloxacin HCl

Norepinephrine bitartrate

Ondansetron HCl

Paclitaxel

Pantoprazole sodium

Phenobarbital sodium

Phenylephrine HCl

Potassium chloride

Ranitidine HCl

Sodium bicarbonate

Sodium phosphates

Tacrolimus

Telavancin HCl

Tigecycline

Tobramycin sulfate

Vancomycin HCl

Voriconazole

Zidovudine

Incompatible

Diazepam

Potassium phosphates

Propofol

Variable

Amphotericin B

Amphotericin B cholesteryl sulfate complex

Amphotericin B lipid complex

Amphotericin B liposomal

Actions and Spectrum

  • Synthetic carbapenem β-lactam antibiotic; structurally and pharmacologically related to ertapenem, imipenem, and meropenem.1 3

  • Usually bactericidal in action.1

  • Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1 3 10

  • Spectrum of activity includes many aerobic and anaerobic gram-positive and gram-negative bacteria.1 3 4 5 10

  • Reported as more active than some other carbapenems against Enterobacteriaceae and Ps. aeruginosa.2 3 4 9 10 12 18

  • Gram-positive aerobes: Active in vitro and in clinical infections against Streptococcus intermedius1 and S. constellatus.1 Also active in vitro against Staphylococcus aureus (including oxacillin-susceptible [methicillin-susceptible] strains),1 4 S. epidermidis,4 S. agalactiae (group B streptococci),1 4 and S. pyogenes (group A β-hemolytic streptococci).1 Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.1

  • Gram-negative aerobes: Active in vitro and in clinical infections against E. coli,1 4 Klebsiella pneumoniae,1 4 Proteus mirabilis,1 4 Ps. aeruginosa,1 4 and Acinetobacter baumannii.1 Also active in vitro against Citrobacter freundii,1 Enterobacter cloacae,1 4 E. aerogenes,1 4 K. oxytoca,1 4 Morganella morganii,1 and Serratia marcescens1 and some strains of Burkholderia cepacia.17 18

  • Anaerobes: Active in vitro and in clinical infections against Bacteroides fragilis,1 4 5 B. caccae,1 4 B. thetaiotaomicron,1 4 5 B. uniformis,1 4 B. vulgatus,1 4 and Peptostreptococcus micros.1 4 5

  • Cross-resistance may occur with other carbapenems; however, some isolates (e.g., some strains of Ps. aeruginosa) resistant to other carbapenems may be susceptible to doripenem.1 4

Advice to Patients

  • Advise patients that antibacterials (including doripenem) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

  • Importance of completing full course of therapy, even if feeling better after a few days.1

  • Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with doripenem or other antibacterials in the future.1

  • Importance of informing clinicians of any previous hypersensitivity reactions to doripenem, other carbapenems, β-lactams, or other allergens.1

  • Importance of discontinuing therapy and informing clinician if an allergic or hypersensitivity reaction occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Doripenem (Monohydrate)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

500 mg (of doripenem)

Doribax

Ortho-McNeil

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 20, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Ortho-McNeil, Inc. Doribax (doripenem for injection) prescribing information. Raritan, NJ; 2008 Jan.

2. Lucasti C, Jasovich A, Umeh O et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther. 2008; 30:868-83. [PubMed 18555934]

3. Zhanel GG, Wiebe R, Dilay L et al. Comparative review of the carbapenems. Drugs. 2007; 67:1027-52. [PubMed 17488146]

4. Goldstein EJ, Citron DM, Merriam CV et al. In vitro activities of doripenem and six comparator drugs against 423 aerobic and anaerobic bacterial isolates from infected diabetic foot wounds. Antimicrob Agents Chemother. 2008; 52:761-6. [PubMed 18070958]

5. Wexler HM, Engel AE, Glass D et al. In vitro activities of doripenem and comparator agents against 364 anaerobic clinical isolates. Antimicrob Agents Chemother. 2005; 49:4413-7. [PubMed 16189137]

6. Ortho-McNeil, Inc, Titusville, NJ: Personal communication.

7. Naber K, Redman R, Kotey P et al. Intravenous therapy with doripenem versus levofloxacin with an option for oral step-down therapy in the treatment of complicated urinary tract infections and pyelonephritis. Int J Antimicrob Agents. 2007; 29:S212.

8. Horiuchi M, Kimura M, Tokumura M et al. Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics. Toxicology. 2006; 222:114-24. [PubMed 16549226]

9. Hagerman JK, Knechtel SA, Klepser ME. Doripenem: a new extended-spectrum carbapenem antibiotic. Formulary. 2007; 42:676-88.

10. Nicolau DP. Carbapenems: a potent class of antibiotics. Expert Opin Pharmacother. 2008; 9:23-37. [PubMed 18076336]

11. Ikawa K, Morikawa N, Urakawa N et al. Peritoneal penetration of doripenem after intravenous administration in abdominal-surgery patients. J Antimicrob Chemother. 2007; 60:1395-7. [PubMed 17884833]

12. Mesaros N, Nordmann P, Plésiat P et al. Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium. Clin Microbiol Infect. 2007; 13:560-78. [PubMed 17266725]

13. Réa-Neto A, Niederman M, Lobo SM et al. Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study. Curr Med Res Opin. 2008; 24:2113-26. [PubMed 18549664]

14. Chastre J, Wunderink R, Prokocimer P et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study. Crit Care Med. 2008; 36:1089-96. [PubMed 18379232]

15. Davies TA, Shang W, Bush K et al. Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2008; 52:1510-2. [PubMed 18250190]

16. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2004 July. From FDA web site (). Accessed August 2008.

17. Chen Y, Garber E, Zhao Q et al. In vitro activity of doripenem (S-4661) against multidrug-resistant gram-negative bacilli isolated from patients with cystic fibrosis. Antimicrob Agents Chemother. 2005; 49:2510-1. [PubMed 15917558]

18. Traczewski MM, Brown SD. In vitro activity of doripenem against Pseudomonas aeruginosa and Burkholderia cepacia isolates from both cystic fibrosis and non-cystic fibrosis patients. Antimicrob Agents Chemother. 2006; 50:819-21. [PubMed 16436756]

19. Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis. 1998; 26:1027-36. [IDIS 407733] [PubMed 9597221]

20. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of America. Position paper on Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995; 16:459-77. [PubMed 7594392]

21. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol. 1997; 92:739-50. [IDIS 386628] [PubMed 9149180]

22. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health-Syst Pharm. 1998; 55:1407-11. [IDIS 407213] [PubMed 9659970]

23. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998; 41(Suppl C):41-6. [IDIS 407246] [PubMed 9630373]

24. Merck & Co., Inc. Invanz (ertapenem) for injection prescribing information. Whitehouse Station, NJ; 2008 Feb.

25. Merck & Co., Inc. Primaxin I.V. (imipenem and cilastatin) for injection prescribing information. Whitehouse Station, NJ; 2007 Dec.

26. AstraZeneca. Merrem I.V. (meropenem) for injection for intravenous use only prescribing information. Wilmington, DE; 2008 Mar.

27. A multicenter, phase 3 study to confirm the safety and efficacy of intravenous doripenem in complicated lower urinary tract infection or pyelonephritis (JNJ-38 174942 DORI-06 CR005398). From National Institutes of Health clinical trials website (). Accessed 2008 Sep 26.

a. Ortho-McNeil, Inc. Doribax (doripenem for injection) prescribing information. Raritan, NJ; 2008 Oct.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-Systems Pharmacists; 2013:407-11.

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