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Doripenem

Pronunciation

(dore i PEN em)

Index Terms

  • S-4661

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Doribax: 250 mg (1 ea); 500 mg (1 ea)

Generic: 250 mg (1 ea); 500 mg (1 ea)

Brand Names: U.S.

  • Doribax

Pharmacologic Category

  • Antibiotic, Carbapenem

Pharmacology

Inhibits bacterial cell wall synthesis by binding to several of the penicillin-binding proteins (PBP-2, PBP-3, PBP-4), which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis; bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Distribution

Penetrates well into body fluids and tissues, including peritoneal and retroperitoneal fluids, gallbladder, bile, and urine; Vd: 16.8 L

Metabolism

Non-CYP-mediated metabolism via hydrolysis by dehydropeptidase-I to doripenem-M1 (inactive metabolite)

Excretion

Urine (71% as unchanged drug; 15% as doripenem-M1 metabolite); feces (<1%)

Half-Life Elimination

~1 hour

Protein Binding

~8.1%

Special Populations: Renal Function Impairment

Following a single 500 mg dose, the mean AUC in subjects with mild, moderate, and severe renal impairment was 1.6, 2.8, and 5.1 times that of age-matched healthy subjects with healthy renal function (CrCl 80 mL/minute or more), respectively.

Use: Labeled Indications

Intra-abdominal infections, complicated: Treatment of complicated intra-abdominal infections caused by Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Escherichia coli, Klebsiella pneumoniae, Peptostreptococcus micros, Pseudomonas aeruginosa, Streptococcus intermedius, and Streptococcus constellatus.

Urinary tract infections, complicated (including pyelonephritis): Treatment of complicated urinary tract infections (UTIs), including pyelonephritis, caused by E. coli (including cases with concurrent bacteremia), Acinetobacter baumannii, K. pneumoniae, Proteus mirabilis, and P. aeruginosa.

Off Label Uses

Catheter-related bloodstream infections (adults)

Doripenem is recommended by IDSA clinical practice guidelines for the management of catheter-related bloodstream infections as a first-line agent for the treatment of catheter-related infections caused by ESBL-producing E. coli and Klebsiella species in adults. The guidelines also list doripenem as an appropriate alternative agent given with an aminoglycoside for catheter-related infections caused by O. anthropi. Doripenem may also be used in the treatment of catheter-related infections caused by susceptible Enterobacter species, S. marcescens, Acinetobacter species, P. aeruginosa, and B. cepacia.

Osteomyelitis, native vertebral

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults, doripenem is an effective and recommended agent for the treatment of native vertebral osteomyelitis due to Pseudomonas aeruginosa.

Contraindications

Known serious hypersensitivity to doripenem, any component of the formulation or other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams

Dosing: Adult

Note: A switch to appropriate oral antimicrobial therapy may be considered after 3 days of parenteral therapy and demonstrated clinical improvement.

Intra-abdominal infection, complicated: IV: 500 mg every 8 hours for 5 to 14 days. Note: IDSA guidelines recommend treatment duration of 4 to 7 days (provided source controlled). Not recommended for mild to moderate, community-acquired intra-abdominal infections (Solomkin 2010).

Urinary tract infection, complicated (including pyelonephritis): IV: 500 mg every 8 hours for 10 days (14 days with concurrent bacteremia).

Urinary tract infection (complicated) or pyelonephritis: IV: 500 mg every 8 hours for 10 to 14 days

Intravenous catheter-related bloodstream infection (off-label use): IV: 500 mg every 8 hours for 7 to 14 days (IDSA, 2009)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Renal function estimated using the Cockcroft-Gault formula:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: 250 mg every 8 hours

CrCl 11 to 29 mL/minute: 250 mg every 12 hours

End-stage renal disease (ESRD) on intermittent hemodialysis (IHD): Dialyzable (~52% of dose removed during 4-hour session in ESRD patients): 250 mg every 24 hours; if treating infections caused by Pseudomonas aeruginosa, administer 500 mg every 12 hours on day 1, followed by 500 mg every 24 hours (Tanoue 2011)

Peritoneal dialysis (PD): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

CVVHD: 1,000 mg every 8 hours (Vossen 2016)

CVVHDF: 250 mg every 12 hours (Hidaka 2010)

Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer’s labeling (has not been studied); however, doripenem undergoes minimal hepatic metabolism.

Reconstitution

Reconstitute 250 mg and 500 mg vial with 10 mL of SWFI or NS; further dilute the 250 mg vial for infusion with 50 mL or 100 mL of NS or D5W. Further dilute the 500 mg vials for infusion with 100 mL of NS or D5W. Shake gently until clear. To prepare a 250 mg dose using a 500 mg vial, reconstitute the 500 mg vial and further dilute with 100 mL of NS or D5W as above: remove and discard 55 mL from the infusion bag (remaining solution contains 250 mg) Variations in color when reconstituted or diluted from colorless to slightly yellow do not affect product potency.

Administration

IV: Infuse over 1 hour.

Storage

Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted vial may be stored for up to 1 hour prior to preparation of infusion solution. Stability of solution when diluted in NS is 12 hours at room temperature or 72 hours at 2°C to 8°C (36°F to 46°F); stability in D5W is 4 hours at room temperature and 24 hours at 2°C to 8°C (36°F to 46°F). Do not freeze.

Drug Interactions

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Probenecid: May increase the serum concentration of Doripenem. This effect is due to probenecid's ability to decrease the active tubular secretion of doripenem. Avoid combination

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Valproate Products: Carbapenems may decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Headache (3% to 16%)

Gastrointestinal: Diarrhea (6% to 12%), nausea (4% to 12%)

1% to 10%:

Cardiovascular: Phlebitis (2% to 8%)

Dermatologic: Skin rash (1% to 6%; includes allergic/bullous dermatitis, erythema, macular/papular eruptions, urticaria, and erythema multiforme), pruritus (1% to 3%)

Gastrointestinal: Oral candidiasis (1% to 3%), Clostridium dificile associated diarrhea (≤1%)

Genitourinary: Vaginal infection (1% to 2%)

Hematologic & oncologic: Anemia (2% to 10%)

Hepatic: Increased serum transaminases (2% to 7%)

<1% (Limited to important or life-threatening): Anaphylaxis, interstitial pneumonitis, leukopenia, neutropenia, renal failure, renal insufficiency, seizure, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, and skin reactions have been reported in patients receiving beta-lactams.

• CNS effects: Carbapenems have been associated with CNS adverse effects, including confusional states; seizures with doripenem have been reported. Use caution with CNS disorders (eg, brain lesions, stroke, or history of seizures) and adjust dose in renal impairment to avoid drug accumulation, which may increase seizure risk. Patients receiving doses >500 mg every 8 hours may also be at increased risk of seizures.

• Superinfection: Use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in patients with moderate-to-severe renal dysfunction.

• Ventilator-associated pneumonia: Not approved for the treatment of pneumonia including hospital-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP). Demonstrated numerically lower cure rate (versus a comparator antibiotic) and increased mortality rate in patients with VAP in a Phase 3 study using a higher dose and fixed 7-day administration (Kollef 2012).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Administer via intravenous infusion only. Per manufacturer’s labeling, investigational experience of doripenem via inhalation resulted in pneumonitis.

Monitoring Parameters

Monitor for signs of anaphylaxis during first dose; periodic renal assessment

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Information related to use during pregnancy has not been located.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, diarrhea, or injection site irritation. Have patient report immediately to prescriber severe loss of strength and energy, seizures, signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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