Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1604
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Lorabid (Capsule)
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Lorabid is administered orally either at least 1 hour prior
to eating or at least 2 hours after eating. The recommended dosages, durations
of treatment, and applicable patient populations are described in the following
chart: Renal Impairment: Lorabid
may be administered to patients with impaired renal function. The usual dose
and schedule may be employed in patients with creatinine clearance levels
of 50 mL/min or greater. Patients with creatinine clearance between 10 and
49 mL/min may be given half of the recommended dose at the usual dosage interval,
or the normal recommended dose at twice the usual dosage interval. Patients
with creatinine clearance levels less than 10 mL/min may be treated with the
recommended dose given every 3 to 5 days; patients on hemodialysis should
receive another dose following dialysis. When only
the serum creatinine is available, the following formula (based on sex, weight,
and age of the patient) may be used to convert this value into creatinine
clearance (CLcr, mL/min). The equation assumes the patient's renal function
is stable. After mixing, the suspension may be kept at room temperature,
15���30��C (59���86��F), for 14 days without significant
loss of potency. Keep tightly closed. Discard unused portion after 14 days.
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Lorabid (loracarbef, USP) is a synthetic��-lactam antibiotic of the carbacephem class for oral administration.
Chemically, carbacephems differ from cephalosporin-class antibiotics in the
dihydrothiazine ring where a methylene group has been substituted for a sulfur
atom. 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-carboxylic
acid, monohydrate. It is a white to off-white solid with a molecular weight
of 367.8. The empirical formula is CHClNO���HO.
The structural formula is: Lorabid Pulvules (loracarbef
capsules, USP) and Lorabid for Oral Suspension (loracarbef for oral suspension,
USP) are intended for oral administration only. Each
Pulvule contains loracarbef equivalent to 200 mg (0.57 mmol) or 400 mg (1.14
mmol) anhydrous loracarbef activity. They also contain cornstarch, dimethicone,
FD&C Blue No. 2, gelatin, iron oxides, magnesium stearate, and titanium
dioxide. After reconstitution, each 5 mL of Lorabid
for Oral Suspension contains loracarbef equivalent to 100 mg (0.286 mmol)
or 200 mg (0.57mmol) anhydrous loracarbef activity. The suspensions also contain
cellulose, F D&C Red No. 40, flavors, methylparaben, propylparaben,
simethicone emulsion, sodium carboxymethylcellulose, sucrose, and xanthan
gum.
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Loracarbef, after oral administration, was approximately
90% absorbed from the gastrointestinal tract. When capsules were taken with
food, peak plasma concentrations were 50% to 60% of those achieved when the
drug was administered to fasting subjects and occurred from 30 to 60 minutes
later. Total absorption, as measured by urinary recovery and area under the
plasma concentration versus time curve (AUC), was unchanged. The effect of
food on the rate and extent of absorption of the suspension formulation has
not been studied to date. The pharmacokinetics of loracarbef
were linear over the recommended dosage range of 200 to 400 mg, with no accumulation
of the drug noted when it was given twice daily. Average
peak plasma concentrations after administration of 200-mg or 400-mg single
doses of loracarbef as capsules to fasting subjects were approximately 8 and
14��g/mL, respectively, and were obtained within 1.2 hours after dosing.
The average peak plasma concentration in adults following a 400-mg single
dose of suspension was 17��g/mL and was obtained within 0.8 hour after
dosing (see Table). Following administration of 7.5 and 15 mg/kg single doses
of oral suspension to children, average peak plasma concentrations were 13
and 19��g/mL, respectively, and were obtained within 40 to 60 minutes. This
increased rate of absorption (suspension>capsule) should be taken into consideration
if the oral suspension is to be substituted for the capsule, and capsules
should not be substituted for the oral suspension in the treatment of otitis
media . The elimination half-life was an average
of 1.0 h in patients with normal renal function. Concomitant administration
of probenecid decreased the rate of urinary excretion and increased the half-life
to 1.5 hours. In subjects with moderate impairment
of renal function (creatinine clearance 10 to 50 mL/min/1.73 m),
following a single 400-mg dose, the plasma half-life was prolonged to approximately
5.6 hours. In subjects with severe renal impairment (creatinine clearance<10 mL/min/1.73 m), the half-life was increased to approximately
32 hours. During hemodialysis the half-life was approximately 4 hours. In
patients with severe renal impairment, the Cmax increased from 15.4��g/mL
to 23��g/mL . In single-dose studies, plasma half-life
and AUC were not significantly altered in healthy elderly subjects with normal
renal function. There is no evidence of metabolism
of loracarbef in humans. Approximately 25% of circulating
loracarbef is bound to plasma proteins. Middle-ear
fluid concentrations of loracarbef were approximately 48% of the plasma concentration
2 hours after drug administration in pediatric patients. The peak concentration
of 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 bactericidal
action by binding to essential target proteins of the bacterial cell wall,
leading to inhibition of cell-wall synthesis. It is stable in the presence
of some bacterial��-lactamases. Loracarbef has been shown to be active
against most strains of the following organisms both in vitro and in clinical
infections :<br/>Gram-positive aerobes:: Staphylococcus aureus (including
penicillinase-producing strains) NOTE: Loracarbef (like
most��-lactam antimicrobials) is inactive against methicillin-resistant
staphylococci. Staphylococcus
saprophyticus Streptococcus
pneumoniae Streptococcus
pyogenes<br/>Gram-negative aerobes:: Escherichia coli Haemophilus influenzae (including��-lactamase-producing
strains) Moraxella (Branhamella)
catarrhalis (including��-lactamase producing strains) The
following in vitro data are available; however, their clinical significance is unknown. Loracarbef
exhibits in vitro minimum inhibitory
concentrations (MIC) of 8��g/mL or less against most strains of the
following organisms; however, the safety and efficacy of loracarbef in treating
clinical infections due to these organisms have not been established in adequate
and well-controlled trials.<br/>Gram-positive aerobes:: Staphylococcus epidermidis Streptococcus
agalactiae (group B streptococci) Streptococcus bovis Streptococci, groups C, F, and G viridans group
streptococci<br/>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.<br/>Anaerobic organisms:: Clostridium perfringens Fusobacterium necrophorum Peptococcus niger Peptostreptococcus intermedius Propionibacterium acnes Susceptibility Testing Diffusion Techniques���Quantitative
methods that require measurement of zone diameters give the most precise estimate
of the susceptibility of bacteria to antimicrobial agents. One such standardized
methodhas been recommended for use with the 30-��g loracarbef
disk. Interpretation involves the correlation of the diameter obtained in
the disk test with MIC for loracarbef. Reports from the laboratory giving
results of the standard single-disk susceptibility test with a 30-��g
loracarbef disk should be interpreted according to the following criteria: A report of���susceptible���implies that the
pathogen is likely to be inhibited by generally achievable blood concentrations.
A report of���moderately susceptible���indicates that inhibitory
concentrations of the antibiotic may be achieved if high dosage is used or
if the infection is confined to tissues and fluids (e.g., urine) in which
high antibiotic concentrations are attained. A report of���resistant���indicates that achievable concentrations of the antibiotic are unlikely to
be inhibitory and other therapy should be selected. Standardized
procedures require the use of laboratory control organisms. The 30-��g
loracarbef disk should give the following zone diameters with the NCCLS approved
procedure: Dilution Techniques���Use a standardized dilution method(broth,
agar, or microdilution) or equivalent with loracarbef powder. The MIC values
obtained should be interpreted according to the following criteria: As with standard diffusion methods, dilution procedures
require the use of laboratory control organisms. Standard loracarbef powder
should give the following MIC values with the NCCLS approved procedure:
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Pulvules: Keep tightly closed. Store at 25��C (77��F); excursion
permitted to 15���30��C (59���86��F) [see USP Controlled
Room Temperature]. Protect from heat. For Oral Suspension
(strawberry bubble gum flavor): Prior to mixing, store at 25��C (77��F); excursion
permitted to 15���30��C (59���86��F) [see USP Controlled
Room Temperature].
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General���In
patients with known or suspected renal impairment , careful clinical observation and appropriate laboratory studies
should be performed prior to and during therapy. The total daily dose of loracarbef
should be reduced in these patients because high and/or prolonged plasma antibiotic
concentrations can occur in such individuals administered the usual doses.
Loracarbef, like cephalosporins, should be given with caution to patients
receiving concurrent treatment with potent diuretics because these diuretics
are suspected of adversely affecting renal function. As
with other broad-spectrum antimicrobials, prolonged use of loracarbef may
result in the overgrowth of nonsusceptible organisms. Careful observation
of the patient is essential. If superinfection occurs during therapy, appropriate
measures should be taken. Loracarbef, as with other
broad-spectrum antimicrobials, should be prescribed with caution in individuals
with a history of colitis. Information for Patients���Lorabid
should be taken either at least 1 hour prior to eating or at least 2 hours
after eating a meal. Drug Interactions��� Probenecid: As with other��-lactam antibiotics, renal
excretion of loracarbef is inhibited by probenecid and resulted in an approximate
80% increase in the AUC for loracarbef . Carcinogenesis, Mutagenesis,
Impairment of Fertility���Although lifetime studies in animals
have not been performed to evaluate carcinogenic potential, no mutagenic potential
was found for loracarbef in standard tests of genotoxicity, which included
bacterial mutation tests and in vitro and in vivo mammalian systems. In rats, fertility
and reproductive performance were not affected by loracarbef at doses up to
33 times the maximum human exposure in mg/kg (10 times the exposure based
on mg/m). Usage in Pregnancy���Pregnancy Category B���Reproduction studies
have been performed in mice, rats, and rabbits at doses up to 33 times the
maximum human exposure in mg/kg (4, 10, and 4 times the exposure, respectively,
based on mg/m) and have revealed no evidence of impaired fertility
or harm to the fetus due to loracarbef. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed. Labor and Delivery���Lorabid
has not been studied for use during labor and delivery. Treatment should be
given only if clearly needed. Nursing Mothers���It
is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when Lorabid is administered
to a nursing woman. Pediatric Use���The
safety and efficacy of Lorabid have been established for pediatric patients
aged six months to twelve years for acute maxillary sinusitis based upon its
approval in adults. Use of Lorabid in pediatric patients is supported by pharmacokinetic
and safety data in adults and children, and by clinical and microbiologic
data from adequate and well-controlled studies of the treatment of acute maxillary
sinusitis in adults and of acute otitis media with effusion in children. It
is also supported by post-marketing adverse events surveillance. (See CLINICAL
PHARMACOLOGY, INDICATIONSAND USAGE,ADVERSE REACTIONS, DOSAGE
AND ADMINISTRATION, and CLINICAL STUDIES sections). Geriatric Use���Healthy
geriatric volunteers (���65 years old) with normal renal function who
received a single 400-mg dose of loracarbef had no significant differences
in AUC or clearance when compared to healthy adult volunteers 20 to 40 years
of age . Of 3541
adult patients in controlled clinical studies of loracarbef, 705 (19.9%) were
65 years of age or older. In these controlled clinical studies, when geriatric
patients received the usual recommended adult doses, clinical efficacy and
safety were comparable to results in non-geriatric patients. Loracarbef
is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function.
Because significant numbers of elderly patients have decreased renal function,
care should be taken in dose selection and evaluation of renal function in
this population is recommended .
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Signs and Symptoms���The
toxic symptoms following an overdose of��-lactams may include nausea,
vomiting, epigastric distress, and diarrhea. Loracarbef
is eliminated primarily by the kidneys. Forced diuresis, peritoneal dialysis,
hemodialysis, or hemoperfusion have not been established as beneficial for
an overdose of loracarbef. Hemodialysis has been shown to be effective in
hastening the elimination of loracarbef from plasma in patients with chronic
renal failure.
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loracarbef
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Lorabid (Capsule)
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The nature of adverse reactions to loracarbef are similar
to those observed with orally administered��-lactam antimicrobials.
The majority of adverse reactions observed in clinical trials were of a mild
and transient nature; 1.5% of patients discontinued therapy because of drug-related
adverse reactions. No one reaction requiring discontinuation accounted for>0.03% of the total patient population; however, of those reactions resulting
in discontinuation, gastrointestinal events (diarrhea and abdominal pain)
and skin rashes predominated.<br/>All Patients: The following adverse events, irrespective of relationship
to drug, have been reported following the use of Lorabid in clinical trials.
Incidence rates (combined for all dosing regimens and dosage forms) were less
than 1% for the total patient population, except as otherwise noted: Gastrointestinal: The most commonly observed adverse
reactions were related to the gastrointestinal system. The incidence of gastrointestinal
adverse reactions increased in patients treated with higher doses. Individual
event rates included diarrhea, 4.1%; nausea, 1.9%; vomiting, 1.4%; abdominal
pain, 1.4%; and anorexia. Hypersensitivity:Hypersensitivity reactions including, skin rashes (1.2%), urticaria,
pruritus, and erythema multiforme. Central
Nervous System: Headache (2.9%), somnolence, nervousness, insomnia,
and dizziness. Hemic and
Lymphatic Systems: Transient thrombocytopenia, leukopenia, and eosinophilia. Hepatic: Transient elevations in AST (SGOT), ALT
(SGPT), and alkaline phosphatase. Renal:Transient elevations in BUN and creatinine. Cardiovascular System: Vasodilatation. Genitourinary: Vaginitis (1.3%), vaginal moniliasis
(1.1%). As with other��-lactam antibiotics, the
following potentially severe adverse experiences have been reported rarely
with loracarbef in worldwide post-marketing surveillance: anaphylaxis, hepatic
dysfunction including cholestasis (with or without jaundice), prolongation
of the prothrombin time with clinical bleeding in patients taking anticoagulants,
and Stevens-Johnson syndrome.<br/>Pediatric Patients: The incidences of several adverse events, irrespective of
relationship to drug, following treatment with Lorabid were significantly
different in the pediatric population and the adult population as follows:<br/>��-Lactam Antimicrobial Class Labeling:: The following adverse reactions and altered laboratory test
results have been reported in patients treated with��-lactam antibiotics: Adverse Reactions���Allergic reactions,
aplastic anemia, hemolytic anemia, hemorrhage, agranulocytosis, toxic epidermal
necrolysis, renal dysfunction, and toxic nephropathy. As with other��-lactam
antibiotics, serum sickness-like reactions have been reported rarely with
loracarbef. Several��-lactam antibiotics have
been implicated in triggering seizures, particularly in patients with renal
impairment when the dosage was not reduced. If seizures associated with drug
therapy should occur, the drug should be discontinued. Anticonvulsant therapy
can be given if clinically indicated. Altered
Laboratory Tests���Increased prothrombin time, positive direct
Coombs' test, elevated LDH, pancytopenia, and neutropenia.
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BEFORE THERAPY WITH LORABID IS INSTITUTED, CAREFUL INQUIRY
SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY
REACTIONS TO LORACARBEF, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS
PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE
EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG��-LACTAM ANTIBIOTICS
HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A
HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO LORABID OCCURS,
DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE
THE USE OF EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS
FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY
MANAGEMENT, AS CLINICALLY INDICATED. Pseudomembranous
colitis has been reported with nearly all antibacterial agents and may range
from mild to life-threatening. Therefore, it is important to consider this
diagnosis in patients who present with diarrhea subsequent to the administration
of antibacterial agents. Treatment with broad-spectrum
antibiotics alters the normal flora of the colon and may permit overgrowth
of clostridia. Studies indicate that a toxin produced by Clostridium
difficile is a primary cause of���antibiotic-associated colitis.��� After
the diagnosis of pseudomembranous colitis has been established, therapeutic
measures should be initiated. Mild cases of pseudomembranous colitis usually
respond to discontinuation of drug alone. In moderate to severe cases, consideration
should be given to management with fluids and electrolytes, protein supplementation,
and treatment with an antibacterial drug effective against C.
difficile-associated colitis.
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Lorabid is indicated in the treatment of patients with mild
to moderate infections caused by susceptible strains of the designated microorganisms
in 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.)<br/>Lower Respiratory Tract: Secondary Bacterial Infection
of Acute Bronchitis caused by S. pneumoniae, H. influenzae (including��-lactamase-producing strains), or M. catarrhalis (including��-lactamase-producing strains). Acute Bacterial Exacerbations
of Chronic Bronchitis caused by S.
pneumoniae, H. influenzae (including��-lactamase-producing strains), or M. catarrhalis (including��-lactamase-producing strains). Pneumonia caused
by S. pneumoniae or H.
influenzae (non-��-lactamase-producing strains only). Data
are insufficient at this time to establish efficacy in patients with pneumonia
caused by��-lactamase-producing strains of H.
influenzae.<br/>Upper Respiratory Tract: Otitis Media���caused by S. pneumonia, H.
influenzae (including��-lactamase-producing strains), M. catarrhalis (including��-lactamase-producing
strains), or S. pyogenes. Acute Maxillary Sinusitis���caused by S. pneumoniae, H. influenzae (non-��-lactamase-producing
strains only), or M. catarrhalis (including��-lactamase-producing strains). Data are insufficient at this time to
establish efficacy in patients with acute maxillary sinusitis caused by��-lactamase-producing
strains of H. influenzae. ���NOTE: In a patient population with significant numbers of��-lactamase-producing
organisms, loracarbef's clinical cure and bacteriological eradication
rates were somewhat less than those observed with a product containing a��-lactamase
inhibtor. Lorabid's decreased potential for toxicity compared to products
containing��-lactamase inhibitors along with the susceptibility patterns
of the common microbes in a given geographic area should be taken into account
when considering the use of an antimicrobial . For information on use in pediatric patients, seePRECAUTIONS���Pediatric
Use. Pharyngitis and Tonsillitis caused by S. pyogenes.
(The usual drug of choice in the treatment and prevention of streptococcal
infections, including the prophylaxis of rheumatic fever, is penicillin administered
by the intramuscular route. Lorabid is generally effective in the eradication
of S. pyogenes from the nasopharynx;
however, data establishing the efficacy of Lorabid in the subsequent prevention
of rheumatic fever are not available at present.)<br/>Skin and Skin Structure: Uncomplicated Skin and
Skin Structure Infections caused by S.
aureus (including penicillinase-producing strains) or S.
pyogenes. Abscesses should be surgically drained as clinically indicated.<br/>Urinary Tract: Uncomplicated Urinary Tract
Infections (cystitis) caused by E.coli or S. saprophyticus*. NOTE:
In considering the use of Lorabid in the treatment of cystitis, Lorabid's
lower bacterial eradication rates and lower potential for toxicity should
be weighed against the increased eradication rates and increased potential
for toxicity demonstrated by some other classes of approved agents . Uncomplicated Pyelonephritis caused by E. coli. *Although treatment
of infections due to this organism in this organ system demonstrated a clinically
acceptable overall outcome, efficacy was studied in fewer than 10 infections. Culture
and susceptibility testing should be performed when appropriate to determine
the causative organism and its susceptibility to loracarbef. Therapy may be
started while awaiting the results of these studies. Once these results become
available, antimicrobial therapy should be adjusted accordingly. CONTRAINDICATION Lorabid
is contraindicated in patients with known allergy to loracarbef or cephalosporin-class
antibiotics.
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Lorabid
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