DESCRIPTION

Lorabid® (loracarbef, USP) is a syntheticβ-lactam antibiotic of the carbacephem class for oral administration.Chemically, carbacephems differ from cephalosporin-class antibiotics in thedihydrothiazine ring where a methylene group has been substituted for a sulfuratom.

The chemical name for loracarbef is: (6R, 7S)-7-[(R)-2-amino-2-phenylacetamido]-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, monohydrate. It is a white to off-white solid with a molecular weightof 367.8. The empirical formula is C16H16ClN3O4•H2O.The structural formula is:

Lorabid Pulvules® (loracarbefcapsules, USP) and Lorabid for Oral Suspension (loracarbef for oral suspension,USP) are intended for oral administration only.

EachPulvule contains loracarbef equivalent to 200 mg (0.57 mmol) or 400 mg (1.14mmol) anhydrous loracarbef activity. They also contain cornstarch, dimethicone,FD & C Blue No. 2, gelatin, iron oxides, magnesium stearate, and titaniumdioxide.

After reconstitution, each 5 mL of Lorabidfor Oral Suspension contains loracarbef equivalent to 100 mg (0.286 mmol)or 200 mg (0.57mmol) anhydrous loracarbef activity. The suspensions also containcellulose, F D & C Red No. 40, flavors, methylparaben, propylparaben,simethicone emulsion, sodium carboxymethylcellulose, sucrose, and xanthangum.

CLINICAL PHARMACOLOGY

Loracarbef, after oral administration, was approximately90% absorbed from the gastrointestinal tract. When capsules were taken withfood, peak plasma concentrations were 50% to 60% of those achieved when thedrug was administered to fasting subjects and occurred from 30 to 60 minuteslater. Total absorption, as measured by urinary recovery and area under theplasma concentration versus time curve (AUC), was unchanged. The effect offood on the rate and extent of absorption of the suspension formulation hasnot been studied to date.

The pharmacokinetics of loracarbefwere linear over the recommended dosage range of 200 to 400 mg, with no accumulationof the drug noted when it was given twice daily.

Averagepeak plasma concentrations after administration of 200-mg or 400-mg singledoses of loracarbef as capsules to fasting subjects were approximately 8 and14 μg/mL, respectively, and were obtained within 1.2 hours after dosing.The average peak plasma concentration in adults following a 400-mg singledose of suspension was 17 μg/mL and was obtained within 0.8 hour afterdosing (see Table).

Following administration of 7.5 and 15 mg/kg single dosesof oral suspension to children, average peak plasma concentrations were 13and 19 μg/mL, respectively, and were obtained within 40 to 60 minutes.

Thisincreased rate of absorption (suspension > capsule) should be taken into considerationif the oral suspension is to be substituted for the capsule, and capsulesshould not be substituted for the oral suspension in the treatment of otitismedia (see DOSAGE AND ADMINISTRATION).

The elimination half-life was an averageof 1.0 h in patients with normal renal function. Concomitant administrationof probenecid decreased the rate of urinary excretion and increased the half-lifeto 1.5 hours.

In subjects with moderate impairmentof renal function (creatinine clearance 10 to 50 mL/min/1.73 m2),following a single 400-mg dose, the plasma half-life was prolonged to approximately5.6 hours. In subjects with severe renal impairment (creatinine clearance<10 mL/min/1.73 m2), the half-life was increased to approximately32 hours. During hemodialysis the half-life was approximately 4 hours. Inpatients with severe renal impairment, the Cmax increased from 15.4 μg/mLto 23 μg/mL (see PRECAUTIONSand DOSAGE AND ADMINISTRATION).

In single-dose studies, plasma half-lifeand AUC were not significantly altered in healthy elderly subjects with normalrenal function.

There is no evidence of metabolismof loracarbef in humans.

Approximately 25% of circulatingloracarbef is bound to plasma proteins.

Middle-earfluid concentrations of loracarbef were approximately 48% of the plasma concentration2 hours after drug administration in pediatric patients. The peak concentrationof loracarbef in blister fluid was approximately half that obtained in plasma.Adequate data on CSF levels of loracarbef are not available.

Microbiology—Loracarbef exerts its bactericidalaction by binding to essential target proteins of the bacterial cell wall,leading to inhibition of cell-wall synthesis. It is stable in the presenceof some bacterial β-lactamases. Loracarbef has been shown to be activeagainst most strains of the following organisms both in vitro and in clinicalinfections (see INDICATIONS AND USAGE):

Gram-positive aerobes:

Staphylococcus aureus (includingpenicillinase-producing strains)

NOTE: Loracarbef (likemost β-lactam antimicrobials) is inactive against methicillin-resistantstaphylococci.

Staphylococcussaprophyticus

Streptococcuspneumoniae

Streptococcuspyogenes

Gram-negative aerobes:

Escherichia coli

Haemophilus influenzae (including β-lactamase-producingstrains)

Moraxella (Branhamella)catarrhalis (including β-lactamase producing strains)

Thefollowing in vitro data are available; however, their clinical significance is unknown.

Loracarbefexhibits in vitro minimum inhibitoryconcentrations (MIC) of 8 μg/mL or less against most strains of thefollowing organisms; however, the safety and efficacy of loracarbef in treatingclinical infections due to these organisms have not been established in adequateand well-controlled trials.

Gram-positive aerobes:

Staphylococcus epidermidis

Streptococcusagalactiae (group B streptococci)

Streptococcus bovis

Streptococci, groups C, F, and G viridans groupstreptococci

Gram-negative aerobes:

Citrobacter diversus

Haemophilus parainfluenzae

Klebsiella pneumoniae

Neisseria gonorrhoeae (including penicillinase-producing strains)

Pasteurella multocida

Proteus mirabilis

Salmonella species

Shigella species

Yersinia enterocolitica

NOTE:Loracarbef is inactive against most strains of Acinetobacter , Enterobacter, Morganella morganii , Proteus vulgaris , Providencia, Pseudomonas , and Serratia.

Anaerobic organisms:

Clostridium perfringens

Fusobacterium necrophorum

Peptococcus niger

Peptostreptococcus intermedius

Propionibacterium acnes

Susceptibility Testing

Diffusion Techniques—Quantitativemethods that require measurement of zone diameters give the most precise estimateof the susceptibility of bacteria to antimicrobial agents. One such standardizedmethod1 has been recommended for use with the 30-μg loracarbefdisk. Interpretation involves the correlation of the diameter obtained inthe disk test with MIC for loracarbef. Reports from the laboratory givingresults of the standard single-disk susceptibility test with a 30-μgloracarbef disk should be interpreted according to the following criteria:

A report of “susceptible” implies that thepathogen is likely to be inhibited by generally achievable blood concentrations.A report of “moderately susceptible” indicates that inhibitoryconcentrations of the antibiotic may be achieved if high dosage is used orif the infection is confined to tissues and fluids (e.g., urine) in whichhigh antibiotic concentrations are attained. A report of “resistant”indicates that achievable concentrations of the antibiotic are unlikely tobe inhibitory and other therapy should be selected.

Standardizedprocedures require the use of laboratory control organisms. The 30-μgloracarbef disk should give the following zone diameters with the NCCLS approvedprocedure:

Dilution Techniques—Use a standardized dilution method2 (broth,agar, or microdilution) or equivalent with loracarbef powder. The MIC valuesobtained should be interpreted according to the following criteria:

As with standard diffusion methods, dilution proceduresrequire the use of laboratory control organisms. Standard loracarbef powdershould give the following MIC values with the NCCLS approved procedure:

INDICATIONS AND USAGE

Lorabid is indicated in the treatment of patients with mildto moderate infections caused by susceptible strains of the designated microorganismsin the conditions listed below. (As recommended dosages, durations of therapy,and applicable patient populations vary among these infections, please see DOSAGE AND ADMINISTRATION for specific recommendations.)

Lower Respiratory Tract

Secondary Bacterial Infectionof Acute Bronchitis caused by S. pneumoniae, H. influenzae (includingβ-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains).

Acute Bacterial Exacerbationsof Chronic Bronchitis caused by S.pneumoniae, H. influenzae (includingβ-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains).

Pneumonia causedby S. pneumoniae or H.influenzae (non-β-lactamase-producing strains only). Dataare insufficient at this time to establish efficacy in patients with pneumoniacaused by β-lactamase-producing strains of H.influenzae.

Upper Respiratory Tract

Otitis Media †caused by S. pneumonia, H.influenzae (including β-lactamase-producing strains), M. catarrhalis (including β-lactamase-producingstrains), or S. pyogenes.

Acute Maxillary Sinusitis† caused by S. pneumoniae, H. influenzae (non-β-lactamase-producingstrains only), or M. catarrhalis (includingβ-lactamase-producing strains). Data are insufficient at this time toestablish efficacy in patients with acute maxillary sinusitis caused by β-lactamase-producingstrains of H. influenzae.

†NOTE: In a patient population with significant numbers of β-lactamase-producingorganisms, loracarbef's clinical cure and bacteriological eradicationrates were somewhat less than those observed with a product containing a β-lactamaseinhibtor. Lorabid's decreased potential for toxicity compared to productscontaining β-lactamase inhibitors along with the susceptibility patternsof the common microbes in a given geographic area should be taken into accountwhen considering the use of an antimicrobial (see CLINICAL STUDIES section). For information on use in pediatric patients, see PRECAUTIONS—PediatricUse.

Pharyngitis and Tonsillitis caused by S. pyogenes.(The usual drug of choice in the treatment and prevention of streptococcalinfections, including the prophylaxis of rheumatic fever, is penicillin administeredby the intramuscular route. Lorabid is generally effective in the eradicationof S. pyogenes from the nasopharynx;however, data establishing the efficacy of Lorabid in the subsequent preventionof rheumatic fever are not available at present.)

Skin and Skin Structure

Uncomplicated Skin andSkin Structure Infections caused by S.aureus (including penicillinase-producing strains) or S.pyogenes. Abscesses should be surgically drained as clinically indicated.

Urinary Tract

Uncomplicated Urinary TractInfections (cystitis) caused by E.coli or S. saprophyticus*.

NOTE:In considering the use of Lorabid in the treatment of cystitis, Lorabid'slower bacterial eradication rates and lower potential for toxicity shouldbe weighed against the increased eradication rates and increased potentialfor toxicity demonstrated by some other classes of approved agents (see CLINICAL STUDIES section).

Uncomplicated Pyelonephritis caused by E. coli.

*Although treatmentof infections due to this organism in this organ system demonstrated a clinicallyacceptable overall outcome, efficacy was studied in fewer than 10 infections.

Cultureand susceptibility testing should be performed when appropriate to determinethe causative organism and its susceptibility to loracarbef. Therapy may bestarted while awaiting the results of these studies. Once these results becomeavailable, antimicrobial therapy should be adjusted accordingly.

CONTRAINDICATION

Lorabidis contraindicated in patients with known allergy to loracarbef or cephalosporin-classantibiotics.

WARNINGS

BEFORE THERAPY WITH LORABID IS INSTITUTED, CAREFUL INQUIRYSHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITYREACTIONS TO LORACARBEF, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THISPRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BEEXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG β-LACTAM ANTIBIOTICSHAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH AHISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO LORABID OCCURS,DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRETHE USE OF EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUSFLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAYMANAGEMENT, AS CLINICALLY INDICATED.

Pseudomembranouscolitis has been reported with nearly all antibacterial agents and may rangefrom mild to life-threatening. Therefore, it is important to consider thisdiagnosis in patients who present with diarrhea subsequent to the administrationof antibacterial agents.

Treatment with broad-spectrumantibiotics alters the normal flora of the colon and may permit overgrowthof clostridia. Studies indicate that a toxin produced by Clostridiumdifficile is a primary cause of “antibiotic-associated colitis.”

Afterthe diagnosis of pseudomembranous colitis has been established, therapeuticmeasures should be initiated. Mild cases of pseudomembranous colitis usuallyrespond to discontinuation of drug alone. In moderate to severe cases, considerationshould be given to management with fluids and electrolytes, protein supplementation,and treatment with an antibacterial drug effective against C.difficile-associated colitis.

PRECAUTIONS

General—Inpatients with known or suspected renal impairment (see DOSAGE AND ADMINISTRATION), careful clinical observation and appropriate laboratory studiesshould be performed prior to and during therapy. The total daily dose of loracarbefshould be reduced in these patients because high and/or prolonged plasma antibioticconcentrations can occur in such individuals administered the usual doses.Loracarbef, like cephalosporins, should be given with caution to patientsreceiving concurrent treatment with potent diuretics because these diureticsare suspected of adversely affecting renal function.

Aswith other broad-spectrum antimicrobials, prolonged use of loracarbef mayresult in the overgrowth of nonsusceptible organisms. Careful observationof the patient is essential. If superinfection occurs during therapy, appropriatemeasures should be taken.

Loracarbef, as with otherbroad-spectrum antimicrobials, should be prescribed with caution in individualswith a history of colitis.

Information for Patients—Lorabidshould be taken either at least 1 hour prior to eating or at least 2 hoursafter eating a meal.

Drug Interactions—

Probenecid: As with other β-lactam antibiotics, renalexcretion of loracarbef is inhibited by probenecid and resulted in an approximate80% increase in the AUC for loracarbef (see CLINICAL PHARMACOLOGY).

Carcinogenesis, Mutagenesis,Impairment of Fertility—Although lifetime studies in animalshave not been performed to eva luate carcinogenic potential, no mutagenic potentialwas found for loracarbef in standard tests of genotoxicity, which includedbacterial mutation tests and in vitro and in vivo mammalian systems.