Maxipime

Generic Name: Cefepime Hydrochloride
Class: Fourth Generation Cephalosporins
Chemical Name: [6R - (6α,7β(Z)]] - 1 - [[7 - [[(2 - amino - 4 - thiazolyl)(methoxyimino)acetyl]amino] - 2 - carboxy - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - en - 3 - yl]methyl] -1-methylpyrrolidinium chloride monohydrochloride monohydrate
Molecular Formula: C₁₉H₂₅ClN₆O₅S₂•HCl•H ₂O
CAS Number: 123171-59-5

Introduction

Antibacterial; β-lactam antibiotic; fourth generation cephalosporin.^{1 2 6}

Uses for Maxipime

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by Escherichia coli, viridans streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter, or Bacteroides fragilis; used in conjunction with IV metronidazole.^{1 37 69 70 92}

Has been used alone for treatment of acute obstetric and gynecologic infections† (e.g., pelvic inflammatory disease [PID], pelvic surgical wound infection, postpartum endometritis),⁴¹ but safety and efficacy of cefepime monotherapy in these infections not established.¹

Respiratory Tract Infections

Treatment of moderate to severe pneumonia (with or without concurrent bacteremia) caused by susceptible Streptococcus pneumoniae.^{1 5 8 14 15 92}

Treatment of moderate to severe pneumonia caused by susceptible P. aeruginosa, K. pneumoniae, or Enterobacter.^{1 5 8 14 15 92}

Treatment of community-acquired pneumonia (CAP)^{40 43} caused by S. pneumoniae, Haemophilus influenzae†, Moraxella catarrhalis†, and Staphylococcus aureus†.⁴³ ATS and IDSA recommend use of cefepime for treatment of CAP only when Ps. aeruginosa is known or suspected to be involved.⁵⁶ For empiric treatment of CAP in patients with risk factors for Ps. aeruginosa, IDSA and ATS recommend a combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (cefepime, imipenem, meropenem, fixed combination of piperacillin and tazobactam) and ciprofloxacin or levofloxacin; one of these β-lactams, an aminoglycoside, and azithromycin; or one of these β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.⁵⁶ If Ps. aeruginosa has been identified by appropriate microbiologic testing, these experts recommend treatment with a regimen that includes an antipseudomonal β-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) and ciprofloxacin, levofloxacin, or an aminoglycoside.⁵⁶

Treatment of nosocomial pneumonia.^{67 68 69} For empiric therapy in severely ill patients or in those with late-onset disease or risk factor for multidrug-resistant bacteria, used in conjunction with either an aminoglycoside (amikacin, gentamicin, tobramycin) or an antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin).⁶⁹ In hospitals where methicillin-resistant (oxacillin-resistant) Staphylococcus is common or if there are risk factors for these strains, initial regimen also should include vancomycin or linezolid.^{67 68 69}

Skin and Skin Structure Infections

Treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (oxacillin-susceptible [methicillin-susceptible] strains only) or susceptible S. pyogenes (group A β-hemolytic streptococci).^{1 3 5 6 7 8 14 17 92}

Urinary Tract Infections (UTIs)

Treatment of mild to moderate uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or with concurrent bacteremia) caused by susceptible E. coli, K. pneumoniae, or Proteus mirabilis.^{1 3 5 6 8 9 16 92}

Treatment of severe uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or concurrent bacteremia) caused by susceptible E. coli or K. pneumoniae.^{1 6 7 14 45 92}

Meningitis and Other CNS Infections

Treatment of meningitis† caused by susceptible gram-negative bacteria (e.g., H. influenzae, Neisseria meningitidis, E. coli, E. aerogenes, Ps. aeruginosa) or gram-positive bacteria (e.g., S. pneumoniae, S. aureus, S. epidermidis).^{46 69 75 77 79 83 84}

Safety and efficacy not established.^{1 92} Manufacturers caution that patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented should receive an alternative anti-infective with demonstrated clinical efficacy in this setting.^{1 92} Some clinicians state additional study is needed regarding efficacy for treatment of meningitis, particularly for infections caused by penicillin- and/or cefotaxime-resistant S. pneumoniae.^{46 79} In addition, cefepime may not be a good choice for empiric treatment of meningitis if Acinetobacter may be involved.⁸³

IDSA states cefepime is one of several alternatives that can be used for treatment of meningitis caused by H. influenzae or E. coli or treatment of meningitis caused by S. pneumonia susceptible to penicillins and third generation cephalosporins.⁷⁵ For treatment of meningitis caused by Ps. aeruginosa, IDSA and other experts recommend a regimen that consists of an antipseudomonal cephalosporin (cefepime or ceftazidime) or carbapenem (imipenem or meropenem) given with or without an aminoglycoside (amikacin, gentamicin, tobramycin).^{69 75 76} Treatment should be guided by results of in vitro susceptibility tests.⁷⁵

IDSA also recommends a regimen of cefepime and vancomycin as one of several regimens that can be used for empiric treatment of penetrating head trauma or postneurosurgical infections caused by S. aureus, coagulase-negative staphylococci (especially S. epidermidis), or aerobic gram-negative bacilli (including Ps. aeruginosa).⁷⁵

Septicemia

Treatment of septicemia† caused by susceptible gram-negative bacteria.⁶⁹

Select anti-infective for treatment of sepsis syndrome based on probable source of infection, gram-stained smears of appropriate clinical specimens, immune status of the patient, and current patterns of bacterial resistance within the hospital and local community.⁶⁹ Some clinicians suggest that certain parenteral cephalosporins (i.e., cefepime, cefotaxime, ceftriaxone, ceftazidime) are good choices for treatment of gram-negative sepsis.⁶⁹

For initial treatment of life-threatening sepsis in adults, some clinicians suggest that a third or fourth generation cephalosporin (i.e., cefepime, cefotaxime, ceftriaxone, ceftazidime), fixed combination of piperacillin and tazobactam, or a carbapenem (imipenem or meropenem) be used in conjunction with vancomycin with or without an aminoglycoside (amikacin, gentamicin, tobramycin).⁶⁹

Empiric Therapy in Febrile Neutropenic Patients

Empiric treatment of presumed bacterial infections in febrile neutropenic patients.^{1 26 34 35 36 58 59 62 69 92}

Has been effective as monotherapy for empiric therapy in febrile neutropenic patients;^{34 35 36 58 59 62} used in conjunction with an aminoglycoside in more seriously ill patients.⁶⁹ Manufacturers caution that safety and efficacy data are limited to date and monotherapy may not be appropriate in patients at severe risk of infection (e.g., those with a history of recent bone marrow transplantation, hypotension on presentation, underlying hematologic malignancy, or severe or prolonged neutropenia).¹

Consult published protocols for the treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.²⁶ Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.^{26 32 38}

Maxipime Dosage and Administration

Administration

Administer by IV infusion or deep IM injection.^{1 2 3 5 6 12 14 92}

IM route should be used only for treatment of mild to moderate, uncomplicated or complicated UTIs caused by E. coli when this route is considered more appropriate.^{1 2 5}

IV Infusion

If a Y-type administration set is used, discontinue other solution flowing through the tubing during cefepime infusion.^{1 2 92}

Manufacturers recommend that aminoglycosides, ampicillin (>40 mg/mL), metronidazole, vancomycin, or aminophylline be administered separately from cefepime.^{1 2 92} (See Drug Compatibility under Compatibility.)

Reconstitution and Dilution

Reconstitute vials for IV infusion with 0.9% sodium chloride, 5 or 10% dextrose, (1/6) M sodium lactate, 5% dextrose and 0.9% sodium chloride, lactated Ringer’s and 5% dextrose injection, Normosol-R, or Normosol-M in 5% dextrose injection.¹

Reconstitute vials containing 500 mg, 1 g, or 2 g of cefepime with 5, 10, or 10 mL of one of these IV solutions, respectively, to provide solutions containing approximately 100, 100, or 160 mg/mL, respectively, and then dilute the appropriate dose in a compatible IV solution.¹

Reconstitute ADD-Vantage vials containing 1 or 2 g of cefepime with 50 or 100 mL of 0.9% sodium chloride or 5% dextrose injection according to the manufacturer’s directions.¹

Thaw the commercially available premixed injection (frozen) at room temperature (25°C) or under refrigeration (5°C); do not thaw by immersion in a water bath or by exposure to microwave radiation.⁹² A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.⁹² Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact or leaks are found.⁹² The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.⁹²

Rate of Administration

Administer by IV infusion over approximately 30 minutes.^{1 92}

IM Injection

Reconstitution

For IM injection, reconstitute vial containing 500 mg or 1 g of cefepime with 1.3 or 2.4 mL, respectively, of sterile water for injection, 0.9% sodium chloride, 5% dextrose, 0.5 or 1% lidocaine hydrochloride, or bacteriostatic water for injection (with parabens or benzyl alcohol) to provide a solution containing approximately 280 mg/mL.^{1 2}

Dosage

Available as cefepime hydrochloride; dosage expressed in terms of cefepime, calculated on the anhydrous basis.^{1 92}

Pediatric Patients

General Pediatric Dosage

IV or IM

Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours.^{1 92}

AAP recommends 100–150 mg/kg daily in 3 divided doses for treatment of mild to moderate infections and 150 mg/kg daily in 3 divided doses for treatment of severe infections in children >1 month of age.⁶⁴

Respiratory Tract Infections

Pneumonia

IV

Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 10 days.^{1 92}

Skin and Skin Structure Infections

Uncomplicated Infections

IV

Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 10 days.^{1 92}

Urinary Tract Infections (UTIs)

Uncomplicated or Complicated UTIs

IV or IM

Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 7–10 days.^{1 92}

Empiric Therapy in Febrile Neutropenic Patients

IV

Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 8 hours for 7 days or until neutropenia resolves.^{1 92}

Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.^{1 92}

Adults

Intra-abdominal Infections

Complicated Infections

IV

2 g every 12 hours for 7–10 days; use in conjunction with IV metronidazole.^{1 92}

Respiratory Tract Infections

Moderate to Severe Pneumonia

IV

1–2 g every 12 hours for 10 days.^{1 92}

1–2 g every 8–12 hours recommended for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia.^{67 92}

Skin and Skin Structure Infections

Moderate to Severe Uncomplicated Infections

IV

2 g every 12 hours for 10 days.^{1 92}

Urinary Tract Infections (UTIs)

Mild to Moderate Uncomplicated or Complicated UTIs

IV or IM

0.5–1 g every 12 hours for 7–10 days.^{1 92}

Severe Uncomplicated or Complicated UTIs

IV

2 g every 12 hours for 10 days.^{1 92}

Empiric Therapy in Febrile Neutropenic Patients

IV

2 g every 8 hours for 7 days or until neutropenia resolves.^{1 34 35 36 92}

Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.^{1 92}

Prescribing Limits

Pediatric Patients

Dosage should not exceed recommended adult dosage.^{1 92}

Special Populations

Hepatic Impairment

Dosage adjustments not required.^{1 92}

Renal Impairment

Dosage adjustments necessary in patients with Cl_cr ≤60 mL/minute.^{1 92}

Adults with Cl_cr ≤60 mL/minute: Give an initial loading dose using the usually recommended adult dosage followed by maintenance dosage based on Cl_cr.^{1 92} (See Table 1 and Table 2.)

Table 1. Maintenance Dosage for Treatment of Infections in Adults with Renal Impairment192

Clcr (mL/minute)	Initial dose: 500 mg	Initial dose: 1 g	Initial dose: 2 g
30–60	500 mg every 24 h	1 g every 24 h	2 g every 24 h
11–29	500 mg every 24 h	500 mg every 24 h	1 g every 24 h
<11	250 mg every 24 h	250 mg every 24 h	500 mg every 24 h

Table 2. Maintenance Dosage for Empiric Therapy in Febrile Neutropenic Adults with Renal Impairment192

Clcr (mL/minute)	Initial Dose: 2 g
30–60	2 g every 12 h
11–29	2 g every 24 h
<11	1 g every 24 h

Adults undergoing hemodialysis: 1 g on the first day of treatment followed by 500 mg every 24 hours for treatment of infections or 1 g on the first day followed by 1 g every 24 hours for empiric therapy in febrile neutropenic patients.^{1 92} Administer the dose at the same time each day (given at completion of procedure on hemodialysis days).^{1 92}

Adults undergoing CAPD: Give usually recommended dose once every 48 hours.^{1 2 6 10 12 92}

Pediatric patients with renal impairment: Dosage adjustments required similar to those recommended for adults.^{1 92}

Cautions for Maxipime

Contraindications

• 
  

  Immediate hypersensitivity to cefepime, other cephalosporins, penicillins, or other β-lactams.^{1 92}

  
  


• 
  

  Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.⁹²

  
  

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Possible emergence and overgrowth of nonsusceptible organisms with prolonged therapy.^{1 92} Careful observation of the patient is essential.^{1 92} Institute appropriate therapy if superinfection occurs.^{1 92}

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.^{1 92} 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, including cefepime, and may range in severity from mild diarrhea to fatal colitis.^{1 92} Hypertoxin producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.^{1 92}

Consider CDAD if diarrhea develops and manage accordingly.^{1 92} Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.^{1 92}

If CDAD is suspected or confirmed may need to discontinue anti-infective therapy not directed against C. difficile.¹ Some mild cases may respond to discontinuance alone.¹ Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.^{1 92}

Neurotoxicity

Serious adverse events, including life-threatening or fatal encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, coma), myoclonus, and seizures reported rarely.^{1 85 86 87 88 92 91} Nonconvulsive status epilepticus, characterized by alteration of consciousness without convulsions that is associated with continuous epileptiform EEG activity, also reported.^{85 91}

Most cases of cefepime-associated neurotoxicity occurred in patients with renal impairment who received dosages of the drug inappropriately high for their renal status;^{1 85 86 87 88 91 92} some cases occurred in patients who received dosage adjusted for renal function^{1 92} or in patients with normal renal function.^{87 88}

Symptoms of neurotoxicity generally were reversible and resolved after cefepime was discontinued and/or after hemodialysis.^{1 92}

If seizures occur, discontinue the drug.^{1 92} Use anticonvulsant therapy if clinically indicated.^{1 92}

Increased Mortality

In November 2007, FDA announced that a safety review of cefepime was initiated after a published meta-analysis described a higher risk of all-cause mortality in patients treated with cefepime compared with patients treated with comparator β-lactams.^{72 73 74} The published meta-analysis looked at all-cause mortality data from 57 randomized controlled trials that compared cefepime with other β-lactams for various indications.⁷¹ FDA began working with Bristol-Myers Squibb to further evaluate the findings presented in the published meta-analysis and additional safety data.^{72 73}

On June 17, 2009, FDA announced that, although the safety review is ongoing, it has determined that cefepime remains an appropriate therapy for its approved indications based on results of FDA's additional meta-analyses.⁷⁴ FDA performed meta-analyses based on both trial- and patient-level data derived from all available cefepime comparative clinical trials.⁷⁴ Results of the trial-level meta-analysis indicated that all-cause mortality rates 30 days after treatment were 6.21% for cefepime-treated patients and 6% for comparator-treated patients.⁷⁴ FDA's patient-level meta-analysis indicated that all-cause mortality rates 30 days after treatment were 5.63% for cefepime-treated patients and 5.68% for comparator-treated patients.⁷⁴ In addition, in a trial-level meta-analysis of 24 febrile neutropenia trials, there was no statistically significant increase in mortality in cefepime-treated patients compared with comparator-treated patients.⁷⁴ A review of deaths reported in 7 of these febrile neutropenia trials indicated that most patients appeared to have died from their underlying malignancies and/or comorbid conditions.⁷⁴

As part of the continuing cefepime safety review, FDA and Bristol-Myers Squibb are in the process of using hospital drug utilization data to conduct additional separate analyses of cefepime-associated mortality.⁷⁴ Results from these studies are unlikely to be available until at least summer 2010.⁷⁴

Sensitivity Reactions

Hypersensitivity Reactions

Possible hypersensitivity reactions, including rash (maculopapular or erythematous), pruritus, fever, eosinophilia, urticaria, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.^{1 92 a}

If an allergic reaction occurs, discontinue cefepime and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).^{1 92}

Cross-hypersensitivity

Partial cross-sensitivity among cephalosporins and other β-lactam antibiotics, including penicillins and cephamycins.^{1 92 a}

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.^{1 92} Cautious use recommended in individuals hypersensitive to penicillins:^{1 92 a} avoid use in those who have had an immediate-type (anaphylactic) hypersensitivity reaction and administer with caution in those who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction.^a

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefepime and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.^{1 92}

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.^{1 92} In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.^{1 92}

History of GI Disease

Use with caution in patients with a history of GI disease, particularly colitis.^{1 92} (See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions.)

Arginine Content

Commercially available cefepime preparations contain l-arginine to adjust pH.^{1 92}

At concentrations 33 times higher than the amount provided by the maximum recommended human cefepime dosage, arginine has altered glucose metabolism and transiently increased serum potassium concentrations.^{1 92} The effect of lower arginine concentrations not known.^{1 92}

Specific Populations

Pregnancy

Category B.^{1 92}

Lactation

Distributed into milk;^{1 6 92} use with caution.^{1 92}

Pediatric Use

Safety and efficacy not established in neonates or infants <2 months of age.^{1 92}

Safety and efficacy have been established for use in pediatric patients 2 months to 16 years of age for treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia and for empiric therapy for febrile neutropenic patients.^{1 92} Use of cefepime in this age group supported by evidence from adequate and well-controlled adult studies and additional pharmacokinetic and safety data from pediatric studies.^{1 92}

Not recommended for treatment of serious infections suspected or known to be caused by Haemophilus influenzae type b (Hib); manufacturers recommend use of an alternative anti-infective if the possibility of meningeal seeding from a distant infection site or meningitis is suspected or documented.^{1 92} (See Uses: Meningitis and Other CNS Infections.)

The commercially available premixed injection (frozen) containing 1 or 2 g of cefepime should not be used in pediatric patients unless the entire 1- or 2-g dose is required.⁹²

Pharmacokinetic and adverse effect profiles similar to those reported in adults.^{1 92}

Geriatric Use

Safety and efficacy in those ≥65 years of age similar to that in younger adults.^{1 92}

Serious adverse effects (including life-threatening or fatal encephalopathy, myoclonus, and seizures) have occurred in geriatric patients who received cefepime dosage inappropriately high for their renal status.^{1 92}

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.^{1 92} Select dosage with caution and assess renal function periodically because of age-related decreases in renal function.^{1 92} (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Pharmacokinetics not affected.^{1 92}

Renal Impairment

Possible decreased clearance and increased serum half-life.^{1 6 92}

Serious adverse events, including life-threatening or fatal encephalopathy, may occur if inappropriately high dosage is used in patients with renal impairment.^{1 85 86 87 91 92} (See Neurotoxicity under Cautions.)

Dosage adjustments necessary in patients with Cl_cr ≤60 mL/minute.^{1 2 92} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,^{1 24 33 92} nausea,^{1 24 33 92} vomiting,^{1 23 33 92} rash,⁹² local reactions (e.g., phlebitis, pain, inflammation).^{1 92}

Interactions for Maxipime

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Aminoglycosides	Possible increased risk of nephrotoxicity and ototoxicity1 92	Closely monitor renal function if used concomitantly1 92
Tests for glucose	Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution1 92 a	Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)1 92 a

Maxipime Pharmacokinetics

Absorption

Bioavailability

Not appreciably absorbed from GI tract; must be administered parenterally.¹

Almost completely absorbed following IM administration;^{1 44} peak serum concentrations attained within 1.4–1.6 hours.¹

Distribution

Extent

Widely distributed into tissues and fluids, including blister fluid,^{1 39 48} bronchial mucosa,¹ sputum,¹ bile,^{1 27} peritoneal fluid,^{1 27} appendix,¹ gallbladder,^{1 27} and prostate.¹

Distributed into CSF following IV administration in adults or pediatric patients.^{1 5 46 78 81 82 84 92}

Distributed into milk.^{1 6}

Plasma Protein Binding

20%.¹

Elimination

Metabolism

Partially metabolized in vivo to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide).¹

Elimination Route

Eliminated principally unchanged in urine by glomerular filtration.^{1 47 49}

In adults with normal renal function, 80–82% of a single dose excreted unchanged in urine;^{1 42 47 49} < 1% of the dose eliminated as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of the drug.¹

Half-life

Adults with normal renal function: 2–2.3 hours.^{1 3 39 49}

Children 2 months to 16 years of age: 1.5-1.9 hours.⁴⁴

Neonates <2 months of age: 4.9 hours.⁸⁰

Special Populations

Pharmacokinetics not affected by hepatic impairment.¹

Patients with renal impairment: Clearance decreased and plasma half-life prolonged.^{1 42} Half-life averages 4.9, 10.5, 13.5 hours in those with Cl_cr 31–60, 11–30, or <10 mL/minute, respectively.⁴²

Stability

Storage

Parenteral

Powder for Injection or Infusion

2–25° C; protect from light.¹

Powder and reconstituted solutions may darken; does not indicate loss of potency.¹

Reconstituted IV solutions containing 1–40 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.¹

IV solutions in ADD-Vantage vials are stable for 24 hours at 20–25°C or 7 days at 2–8°C at concentrations of 10–40 mg/mL in 0.9% sodium chloride or 5% dextrose injection.¹

Reconstituted IM solutions containing 280 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.^{1 2}

Injection (Frozen) for IV Infusion

-20°C or lower.⁹² Thawed solutions are stable for 24 hours at room temperature (25°C) or 7 days under refrigeration (5°C).⁹²

Do not refreeze after thawing.⁹²

Compatibility

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

Parenteral

Solution Compatibility

Compatible
Amino acids 4.25%, dextrose 25% with electrolytesHID
Dextrose 5% in Ringer’s injection, lactated1 HID
Dextrose 5% in sodium chloride 0.9%1 HID
Dextrose 5 or 10% in water1 HID
Normosol M in dextrose 5%1 HID
Normosol R1 HID
Normosol R in dextrose 5%
Sodium chloride 0.9%1 HID

Drug Compatibility

Admixture CompatibilityHID

Compatible
Amikacin sulfate
Clindamycin phosphate
Heparin sodium
Potassium chloride
Theophylline
Vancomycin HCl
Incompatible
Aminophylline
Gentamicin sulfate
Tobramycin sulfate
Variable
Ampicillin sodium
Metronidazole
Metronidazole HCl

Y-Site CompatibilityHID

Compatible
Amikacin sulfate
Ampicillin sodium–sulbactam sodium
Anidulafungin
Aztreonam
Bivalirudin
Bleomycin sulfate
Bumetanide
Buprenorphine HCl
Butorphanol tartrate
Calcium gluconate
Carboplatin
Carmustine
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dactinomycin
Dexamethasone sodium phosphate
Dexmedetomidine HCl
Docetaxel
Doxorubicin HCl liposome injection
Fenoldopam mesylate
Fluconazole
Fludarabine phosphate
Fluorouracil
Furosemide
Gentamicin sulfate
Granisetron HCl
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Imipenem–cilastatin sodium
Leucovorin calcium
Lorazepam
Melphalan
Mesna
Methotrexate sodium
Methylprednisolone sodium succinate
Metronidazole
Milrinone lactate
Paclitaxel
Piperacillin sodium–tazobactam sodium
Ranitidine HCl
Remifentanil HCI
Sargramostim
Sodium bicarbonate
Sufentanil citrate
Thiotepa
Ticarcillin disodium–clavulanate potassium
Tobramycin sulfate
Valproate sodium
Zidovudine
Incompatible
Acetylcysteine
Acyclovir sodium
Amphotericin B
Amphotericin B cholesteryl sulfate complex
Chlordiazepoxide HCl
Chlorpromazine HCl
Cimetidine HCl
Ciprofloxacin
Cisplatin
Dacarbazine
Daunorubicin HCl
Diazepam
Diphenhydramine HCl
Doxorubicin HCl
Droperidol
Enalaprilat
Erythromycin lactobionate
Etoposide
Etoposide phosphate
Famotidine
Filgrastim
Floxuridine
Gallium nitrate
Ganciclovir sodium
Haloperidol lactate
Hydroxyzine HCl
Idarubicin HCl
Ifosfamide
Lansoprazole
Magnesium sulfate
Mannitol
Mechlorethamine HCl
Meperidine HCl
Metoclopramide HCl
Midazolam HCI
Mitomycin
Mitoxantrone HCl
Nalbuphine HCl
Nicardipine HCI
Ofloxacin
Ondansetron HCl
Phenytoin sodium
Plicamycin
Prochlorperazine edisylate
Promethazine HCl
Streptozocin
Theophylline
Vinblastine sulfate
Vincr