LORABID

Lorabid^® (loracarbef, USP) is a syntheticβ-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 C₁₆H₁₆ClN₃O₄•H₂O. 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.

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 μg/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 μg/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 μg/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 (see DOSAGE AND ADMINISTRATION).

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 m²), 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 m²), 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 μg/mL to 23 μg/mL (see PRECAUTIONSandDOSAGE AND ADMINISTRATION).

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 buler 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 β-lactamases. Loracarbef has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE):

Staphylococcus aureus (including penicillinase-producing strains)

NOTE: Loracarbef (like most β-lactam antimicrobials) is inactive against methicillin-resistant staphylococci.

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Escherichia coli

Haemophilus influenzae (including β-lactamase-producing strains)

Moraxella (Branhamella) catarrhalis (including β-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 μg/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.

Staphylococcus epidermidis

Streptococcus agalactiae (group B streptococci)

Streptococcus bovis

Streptococci, groups C, F, and G viridans group streptococci

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.

Clostridium perfringens

Fusobacterium necrophorum

Peptococcus niger

Peptostreptococcus intermedius

Propionibacterium acnes

Susceptibility Testing

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

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.

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 (see CLINICAL STUDIES section).

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.

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 β-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.

The nature of adverse reactions to loracarbef are similar to those observed with orally administered β-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.

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 β-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.

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:

The following adverse reactions and altered laboratory test results have been reported in patients treated with β-lactam antibiotics:

Adverse Reactions—Allergic reactions, aplastic anemia, hemolytic anemia, hemorrhage, agranulocytosis, toxic epidermal necrolysis, renal dysfunction, and toxic nephropathy. As with other β-lactam antibiotics, serum sickness-like reactions have been reported rarely with loracarbef.

Several β-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.

Signs and Symptoms—The toxic symptoms following an overdose of β-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.

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:

Pulvules:

•   200 mg, (blue and gray) (100s) NDC 61570-170-01.
•   400 mg, (blue and pink) (100s) NDC 61570-171-01.

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):

•   100 mg/5 mL, (100-mL size) NDC 61570-135-10
•   200 mg/5 mL, (100-mL size) NDC 61570-136-10

Prior to mixing, store at 25°C (77°F); excursion permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

In a controlled clinical study of acute maxillary sinusitis performed in Europe, loracarbef was compared to doxycycline. In this study there were 210 sinus-puncture evaluable patients. As expected in a European population, this study population had a lower incidence of β-lactamase-producing organisms than usually seen in U.S. trials. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 1- to 2-week post therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (ie, clinical success) were obtained:

• National Committee for Clinical Laboratory Standards, M2- A4 performance standards for antimicrobial disk susceptibility tests. ed 4, Villanova, PA, April, 1990.
• National Committee for Clinical Laboratory Standards, M7-A2 methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. ed 2, Villanova, PA, April, 1990.

Rx Only.

Prescribing Information as of September 2002

Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620

Manufactured by: Eli Lilly Italia, S.p.A., Sesto Fiorentino (Firenze), Italy