Doripenem

Trade Names:
Doribax
- Injection, powder for solution, concentrate 500 mg

Pharmacology

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Inhibits bacterial cell wall biosynthesis, resulting in cell death.

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 t _½ 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

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 function impairment.

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

No dosage adjustments are recommended based on gender.

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. To reduce the development of drug-resistant bacteria and maintain effectiveness of doripenem and other antibacterial agents, use only to treat infections proven or strongly suspected to be caused by susceptible bacteria.

Contraindications

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

Dosage and Administration

IV 500 mg, infused over 1 h, every 8 h for 5 to 14 days.

IV 500 mg, infused over 1 h, every 8 h for 10 days. Duration may be extended to 14 days for patients with concurrent bacteremia.

IV CrCl 30 to 50 mL/min or less: 250 mg, infused over 1 h, every 8 h; CrCl greater than 10 to less than 30 mL/min: 250 mg, infused over 1 h, every 12 h.

General Advice

• Product does not contain a bacteriostatic preservative.
• To prepare 500 mg dose: constitute with 10 mL of sterile water for injection or sodium chloride 0.9% injection, gently shaking vial to form a suspension (concentration, 50 mg/mL). Withdraw suspension and add to infusion bag containing normal saline 100 mL or dextrose 5%, gently shaking until clear (concentration, 4.5 mg/mL).
• To prepare 250 mg dose: constitute with 10 mL of sterile water for injection or sodium chloride 0.9% injection, gently shaking vial to form a suspension (concentration, 50 mg/mL). Withdraw suspension and add to infusion bag containing normal saline 100 mL or dextrose 5%, gently shaking until clear (concentration, 4.5 mg/mL). Remove 55 mL of this solution from bag and discard. Infuse remaining solution (concentration, 4.5 mg/mL).
• 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 at 59° to 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 8 h (includes infusion time) or under refrigeration for 24 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).

Drug Interactions

Doripenem plasma levels may be increased and prolonged because of interference with active tubular secretion by probenecid.

Valproic acid serum concentrations may be reduced to subtherapeutic levels, resulting in loss of seizure control. If serum valproic acid levels cannot be maintained in the therapeutic range or if seizures occur, consider alternative antibacterial or anticonvulsant therapy.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Headache (16%); seizures (postmarketing).

Dermatologic

Rash, including allergic dermatitis (5%); pruritus (3%); Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

GI

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

Genitourinary

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

Hematologic-Lymphatic

Anemia (10%).

Hypersensitivity

Anaphylaxis (postmarketing).

Lab Tests

Elevated hepatic enzymes (2%).

Respiratory

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.

Renal Function

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

Superinfection

May result in bacterial or fungal overgrowth of nonsusceptible organisms.

Pseudomembranous colitis

Consider possibility in patients with diarrhea.

Overdosage

Symptoms

Discontinue doripenem and administer supportive treatment.

Patient Information

• Advise patients that it is common to feel better early in the course of therapy, but medication should be used as directed for the full course of therapy.

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