Doripenem

Pronunciation: DOR-i-PEN-em
Class: Carbapenem antibiotic

Trade Names

Doribax
- Injection, powder for solution 250 mg
- Injection, powder for solution 500 mg

Pharmacology

Inactivates penicillin-binding proteins, resulting in inhibition of bacterial cell wall biosynthesis and cell death.

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Pharmacokinetics

Absorption

Pharmacokinetics are linear over a dose range of 500 to 1,000 mg IV over 1 h. Following a single 1 h IV infusion of 500 mg, the mean plasma C _max and AUC are 23 mcg/mL and 36.3 mcg•h/mL, respectively.

Distribution

Average plasma protein binding is approximately 8%. Vd is 16.8 L. Doripenem penetrates into several body fluids and tissues, including those at the site of infection for approved indications.

Metabolism

Metabolized to an inactive ring-opened metabolite by dehydropeptidase I. Doripenem is not a substrate for hepatic CYP-450 enzymes.

Elimination

Terminal plasma half-life is approximately 1 h. Mean plasma Cl is 15.9 L/h, and mean renal Cl is 10.8 L/h. Within 48 h, approximately 70% is excreted unchanged by the kidneys and 15% as the ring-opened metabolite. Less than 1% excreted in feces after 1 wk.

Special Populations

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/min or more), respectively. Dosage adjustment is necessary in patients with moderate and severe renal function impairment.

Not established; however, because doripenem does not undergo hepatic metabolism, the pharmacokinetics are not expected to be affected by hepatic impairment.

No dosage adjustments are needed in elderly patients with healthy renal function.

C _max and AUC were similar between men and women. No dosage adjustments are recommended based on gender.

No significant difference in mean Cl was observed. No dosage adjustments are recommended based on race.

Indications and Usage

As a single-agent for the treatment of complicated intra-abdominal infections and complicated UTIs, including pyelonephritis, caused by susceptible strains of specific microorganisms.

Unlabeled Uses

Catheter-related bloodstream infection, community-acquired pneumonia, hospital-acquired pneumonia.

Contraindications

Known serious hypersensitivity to doripenem or other carbapenem antibiotics or demonstrated anaphylactic reactions to beta-lactams.

Dosage and Administration

IV 500 mg every 8 h for 5 to 14 days.

IV 500 mg every 8 h for 10 days. Duration may be extended to 14 days for patients with concurrent bacteremia.

250 mg every 8 h.

250 mg every 12 h.

General Advice

• Follow manufacturer's instructions for reconstitution and dilution. Product does not contain a bacteriostatic preservative.
• Administer by IV infusion over 1 h.
• Do not mix product with or physically add to solutions containing other drugs.
• Consider a switch to appropriate oral therapy after at least 3 days of parenteral therapy once clinical improvement has been demonstrated.

Storage/Stability

Store vial between 59° and 86°F. Constituted suspension in vial may be stored for 1 h prior to dilution in infusion bag. Infusion solution prepared in normal saline may be stored at room temperature for 12 h (includes infusion time) or under refrigeration for 72 h (includes infusion time). Infusion solution prepared in dextrose 5% may be stored at room temperature for 4 h (includes infusion time) or under refrigeration for 24 h (includes infusion time). Do not freeze.

Drug Interactions

Doripenem plasma levels may be increased because probenecid interferes with active tubular secretion of doripenem. Coadministration is not recommended.

Valproic acid serum concentrations may be reduced to subtherapeutic levels, resulting in loss of seizure control. Monitor valproic acid plasma concentrations and observe the patient for seizure activity. Consider adjusting the valproic acid dose as needed or using an alternative antibiotic. If doripenem therapy is necessary, consider supplemental anticonvulsant therapy.

Adverse Reactions

CNS

Headache (16%); seizures (postmarketing).

Dermatologic

Rash (5%); pruritus (3%); Stevens-Johnson syndrome, TEN (postmarketing).

GI

Nausea (12%); diarrhea (11%); oral candidiasis (1%).

Genitourinary

Vulvomycotic infection (2%); renal function impairment/renal failure (1%).

Hematologic-Lymphatic

Anemia (10%); leukopenia, neutropenia, thrombocytopenia (postmarketing).

Hypersensitivity

Anaphylaxis (postmarketing).

Lab Tests

Elevated hepatic enzymes (2%).

Respiratory

Pneumonitis (with inhalational use); interstitial pneumonia (postmarketing).

Miscellaneous

Phlebitis (8%).

Precautions

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Because elderly patients are more likely to have decreased renal function or prerenal azotemia, select dose with care.

Hypersensitivity

Serious and occasionally fatal anaphylactic and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. Use with caution if given to a penicillin- or other beta-lactam–allergic patient; cross-hyperreactivity has been documented.

Renal Function

Dosage adjustment is needed in patients with moderate and severe renal impairment.

Superinfection

May result in bacterial or fungal overgrowth of nonsusceptible organisms.

Clostridium difficile –associated diarrhea

Consider possibility in patients with diarrhea.

Patient Information

• Advise patient to notify health care provider if infection does not improve or appears to worsen.
• Instruct patient to report the following symptoms to health care provider: black, furry tongue; diarrhea; difficulty breathing; hives; itching; loose, foul-smelling, watery, or bloody stools; rash; vaginal itching or discharge.
• Warn patient, family, or caregiver that if diarrhea containing blood or pus develops after discharge, it may be a sign of a serious disorder. Instruct patient to seek medical care if noted and not to treat at home.
• Advise patient to inform health care provider if they are taking valproic acid or divalproex sodium for seizures. Therapy modifications may be needed.

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