DRUGS & SUPPLEMENTS

Benaxona

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Benaxona uses



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To reduce the development of drug-resistant bacteria and maintain the effectiveness of Benaxona for Injection, USP and other antibacterial drugs, Benaxona for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Benaxona for Injection, USP is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. Benaxona sodium is (6 R,7 R )-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- as -triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-( Z )-( O -methyloxime), disodium salt, sesquaterhydrate.

The chemical formula of Benaxona sodium is C18H16N8Na2O7S3-3.5H2O. It has a calculated molecular weight of 661.59 and the following structural formula:

Benaxona for Injection, USP is a white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 1% aqueous solution is approximately 6.7. The color of Benaxona for Injection, USP solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used. Each vial contains Benaxona sodium equivalent to 250 mg, 500 mg, 1 gram or 2 grams of Benaxona activity. Benaxona for Injection, USP contains approximately 83 mg (3.6 mEq) of sodium per gram of Benaxona activity.

ceftriaxone-chemical-structure

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CLINICAL PHARMACOLOGY

Average plasma concentrations of Benaxona following a single 30 minute intravenous (IV) infusion of a 0.5, 1 or 2 gm dose and intramuscular (IM) administration of a single 0.5 (250 mg/mL or 350 mg/mL concentrations) or 1 gm dose in healthy subjects are presented in Table 1.

*IV doses were infused at a constant rate over 30 minutes.

ND = Not determined.


Dose/Route


Average Plasma Concentrations (mcg/mL)


0.5 hr


1 hr


2 hr


4 hr


6 hr


8 hr


12 hr


16 hr


24 hr


0.5 gm IV*


82


59


48


37


29


23


15


10


5


0.5 gm IM


250 mg/mL


22


33


38


35


30


26


16


ND


5


0.5 gm IM


350 mg/mL


20


32


38


34


31


24


16


ND


5


1 gm IV*


151


111


88


67


53


43


28


18


9


1 gm IM


40


68


76


68


56


44


29


ND


ND


2 gm IV*


257


192


154


117


89


74


46


31


15


Benaxona was completely absorbed following IM administration with mean maximum plasma concentrations occurring between 2 and 3 hours post-dose. Multiple IV or IM doses ranging from 0.5 to 2 gm at 12 to 24 hour intervals resulted in 15% to 36% accumulation of Benaxona above single dose values.

Benaxona concentrations in urine are shown in Table 2.

ND = Not determined.

Dose/Route


Average Urinary Concentrations (mcg/mL)




0 to 2 hr


2 to 4 hr


4 to 8 hr


8 to 12 hr


12 to 24 hr


24 to 48 hr


0.5 gm IV


526


366


142


87


70


15


0.5 gm IM


115


425


308


127


96


28


1 gm IV


995


855


293


147


132


32


1 gm IM


504


628


418


237


ND


ND


2 gm IV


2692


1976


757


274


198


40


Thirty-three percent to 67% of a Benaxona dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. After a 1 gm IV dose, average concentrations of Benaxona, determined from 1 to 3 hours after dosing, were 581 mcg/mL in the gallbladder bile, 788 mcg/mL in the common duct bile, 898 mcg/mL in the cystic duct bile, 78.2 mcg/gm in the gallbladder wall and 62.1 mcg/mL in the concurrent plasma.

Over a 0.15 to 3 gm dose range in healthy adult subjects, the values of elimination half-life ranged from 5.8 to 8.7 hours; apparent volume of distribution from 5.78 to 13.5 L; plasma clearance from 0.58 to 1.45 L/hour; and renal clearance from 0.32 to 0.73 L/hour. Benaxona is reversibly bound to human plasma proteins, and the binding decreased from a value of 95% bound at plasma concentrations of <25 mcg/mL to a value of 85% bound at 300 mcg/mL. Benaxona crosses the blood placenta barrier.

The average values of maximum plasma concentration, elimination half-life, plasma clearance and volume of distribution after a 50 mg/kg IV dose and after a 75 mg/kg IV dose in pediatric patients suffering from bacterial meningitis are shown in Table 3. Benaxona penetrated the inflamed meninges of infants and pediatric patients; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV dose are also shown in Table 3.




50 mg/kg IV


75 mg/kg IV


Maximum Plasma Concentrations (mcg/mL)


216


275


Elimination Half-life (hr)


4.6


4.3


Plasma Clearance (mL/hr/kg)


49


60


Volume of Distribution (mL/kg)


338


373


CSF Concentration-inflamed meninges (mcg/mL)


5.6


6.4


Range (mcg/mL)


1.3 to 18.5


1.3 to 44


Time after dose (hr)


3.7 (± 1.6)


3.3 (± 1.4)


Compared to that in healthy adult subjects, the pharmacokinetics of Benaxona were only minimally altered in elderly subjects and in patients with renal impairment or hepatic dysfunction (Table 4); therefore, dosage adjustments are not necessary for these patients with Benaxona dosages up to 2 gm per day. Benaxona was not removed to any significant extent from the plasma by hemodialysis. In 6 of 26 dialysis patients, the elimination rate of Benaxona was markedly reduced.


Subject Group


Elimination

Half-Life

(hr)


Plasma

Clearance

(L/hr)


Volume of

Distribution

(L)


Healthy Subjects


5.8 to 8.7


0.58 to 1.45


5.8 to 13.5


Elderly Subjects (mean age, 70.5 yr)


8.9


0.83


10.7


Patients With Renal Impairment








Hemodialysis Patients (0 to 5 mL/min)Creatinine clearance.


14.7


0.65


13.7


Severe (5 to 15 mL/min)


15.7


0.56


12.5


Moderate (16 to 30 mL/min)


11.4


0.72


11.8


Mild (31 to 60 mL/min)


12.4


0.7


13.3


Patients With Liver Disease


8.8


1.1


13.6


The elimination of Benaxona is not altered when Benaxona for injection is co-administered with probenecid.

Pharmacokinetics in the Middle Ear Fluid

In one study, total Benaxona concentrations (bound and unbound) were measured in middle ear fluid obtained during the insertion of tympanostomy tubes in 42 pediatric patients with otitis media. Sampling times were from 1 to 50 hours after a single intramuscular injection of 50 mg/kg of Benaxona. Mean (± SD) Benaxona levels in the middle ear reached a peak of 35 (± 12) mcg/mL at 24 hours, and remained at 19 (± 7) mcg/mL at 48 hours. Based on middle ear fluid Benaxona concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time intervals, a half-life of 25 hours was calculated. Benaxona is highly bound to plasma proteins. The extent of binding to proteins in the middle ear fluid is unknown.

Interaction with Calcium

Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of Benaxona and calcium. Benaxona concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams Benaxona infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of Benaxona from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation.

Microbiology

Mechanism of Action

Benaxona is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Benaxona has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Mechanism of Resistance

Resistance to Benaxona is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Interaction with Other Antimicrobials

In an in vitro study antagonistic effects have been observed with the combination of chloramphenicol and Benaxona.

Benaxona has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

- Gram-negative bacteria

Acinetobacter calcoaceticus

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Neisseria meningitidis

Proteus mirabilis

Proteus vulgaris

Pseudomonas aeruginosa

Serratia marcescens

- Gram-positive bacteria

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans group streptococci

- Anaerobic bacteria

Bacteroides fragilis

Clostridium species

Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for Benaxona. However, the efficacy of Benaxona in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

- Gram-negative bacteria

Citrobacter diversus

Citrobacter freundii

Providencia species (including Providencia rettgeri)

Salmonella species (including Salmonella typhi)

Shigella species

- Gram-positive bacteria

Streptococcus agalactiae

- Anaerobic bacteria

Porphyromonas (Bacteroides) melaninogenicus

Prevotella (Bacteroides) bivius

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 1,3. The MIC values should be interpreted according to criteria provided in Table 5.

Diffusion techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2,3. This procedure uses paper disks impregnated with 30 mcg Benaxona to test the susceptibility of microorganisms to Benaxona. The disk diffusion interpretive criteria are provided in Table 5.

Anaerobic techniques

For anaerobic bacteria, the susceptibility to Benaxona as MICs can be determined by a standardized agar test method 3,4. The MIC values obtained should be interpreted according to the criteria provided in Table 5.

a Susceptibility interpretive criteria for Enterobacteriaceae are based on a dose of 1 gram IV q 24h. For isolates with intermediate susceptibility, use a dose of 2 grams IV q 24h in patients with normal renal function.

b For Haemophilus influenzae, susceptibility interpretive criteria are based on a dose of 2 grams IV every 24 hours in patients with normal renal function.

c The current absence of data on resistant isolates precludes defining any category other than 'Susceptible'. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.

d Disc diffusion interpretive criteria for Benaxona discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of ≥20 mm are susceptible (MIC ≤0.06 mcg/mL) to penicillin and can be considered susceptible to Benaxona. Streptococcus pneumoniae isolates should not be reported as penicillin (ceftriaxone) resistant or intermediate based solely on an oxacillin zone diameter of ≤19 mm. The Benaxona MIC should be determined for those isolates with oxacillin zone diameters ≤19 mm.


Pathogen


Minimum Inhibitory

Concentrations

(mcg/ml)


Disk Diffusion Zone

Diameters (mm)


(S)

Susceptible


(I)

Intermediate


(R)

Resistant


(S)

Susceptible


(I)

Intermediate


(R)

Resistant


Enterobacteriaceaea


≤1


2


≥4


≥23


20 to 22


≤19


Haemophilus

influenzae b, c


≤2


-


-


≥26


-


-


Neisseria gonorrhoeae c


≤0.25


-


-


≥35


-


-


Neisseria meningitidis c


≤0.12


-


-


≥34


-


-


Streptococcus

pneumoniaed

meningitis isolates


≤0.5


1


≥2


-


-


-


Streptococcus

pneumoniae d

non-meningitis

isolates


≤1


2


≥4


-


-


-


Streptococcus

species

betahemolytic

groupc


≤0.5


-


-


≥24


-


-


Viridans group

streptococci


≤1


2


≥4


≥27


25 to 26


≤24


Anaerobic bacteria

(agar method)


≤1


2


≥4


-


-


-


Susceptibility of staphylococci to Benaxona may be deduced from testing only penicillin and either cefoxitin or oxacillin.

A report of Susceptible indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test1,2,3,4. Standard Benaxona powder should provide the following range of MIC values noted in Table 6. For the diffusion technique using the 30 mcg disk, the criteria in Table 6 should be achieved.


QC Strain


Minimum

Inhibitory

Concentrations

(mcg/mL)


Disk

Diffusion

Zone diameters

(mm)


Escherichia coli ATCC 25922


0.03 to 0.12


29 to 35


Staphylococcus aureus ATCC 25923


---------


22 to 28


Staphylococcus aureus ATCC 29213


1 to 8


---------


Haemophilus influenzae ATCC 49247


0.06 to 0.25


31 to 39


Neisseria gonorrhoeae ATCC 49226


0.004 to 0.015


39 to 51


Pseudomonas aeruginosa ATCC 27853


8 to 64


17 to 23


Streptococcus pneumoniae ATCC 49619


0.03 to 0.12


30 to 35


Bacteroides fragilis ATCC 25285 (agar method)


32 to 128


---------


Bacteroides thetaiotaomicron ATCC 29741 (agar method)


64 to 256


---------

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INDICATIONS AND USAGE

Before instituting treatment with Benaxona for Injection, USP appropriate specimens should be obtained for isolation of the causative organism and for determination of its susceptibility to the drug. Therapy may be instituted prior to obtaining results of susceptibility testing.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Benaxona for Injection, USP and other antibacterial drugs, Benaxona for Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Benaxona for Injection, USP is indicated for the treatment of the following infections when caused by susceptible organisms:

LOWER RESPIRATORY TRACT INFECTIONS caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or Serratia marcescens.

ACUTE BACTERIAL OTITIS MEDIA caused by Streptococcus pneumoniae, Haemophilus influenzae (including beta-lactamase producing strains) or Moraxella catarrhalis (including beta-lactamase producing strains).

NOTE: In one study lower clinical cure rates were observed with a single dose of Benaxona for Injection, USP compared to 10 days of oral therapy. In a second study comparable cure rates were observed between single dose Benaxona for Injection, USP and the comparator. The potentially lower clinical cure rate of Benaxona for Injection, USP should be balanced against the potential advantages of parenteral therapy (see CLINICAL STUDIES ).

SKIN AND SKIN STRUCTURE INFECTIONS caused by Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Morganella morganii,* Pseudomonas aeruginosa, Serratia marcescens, Acinetobacter calcoaceticus, Bacteroides fragilis* or Peptostreptococcus species.

URINARY TRACT INFECTIONS (complicated and uncomplicated) caused by Escherichia coli, Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.

UNCOMPLICATED GONORRHEA (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains, and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria gonorrhoeae.

PELVIC INFLAMMATORY DISEASE caused by Neisseria gonorrhoeae. Benaxona for Injection, USP like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and Chlamydia trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.

BACTERIAL SEPTICEMIA caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.

BONE AND JOINT INFECTIONS caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae or Enterobacter species.

INTRA-ABDOMINAL INFECTIONS caused by Escherichia coli, Klebsiella pneumoniae, Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium difficile are resistant) or Peptostreptococcus species.

MENINGITIS caused by Haemophilus influenzae, Neisseria meningitidis or Streptococcus pneumoniae. Benaxona for Injection, USP has also been used successfully in a limited number of cases of meningitis and shunt infection caused by Staphylococcus epidermidis * and Escherichia coli. *

*Efficacy for this organism in this organ system was studied in fewer than ten infections.

SURGICAL PROPHYLAXIS: The preoperative administration of a single 1 gm dose of Benaxona for Injection, USP may reduce the incidence of postoperative infections in patients undergoing surgical procedures classified as contaminated or potentially contaminated (e.g. , vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous cholecystitis in high-risk patients, such as those over 70 years of age, with acute cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common duct bile stones) and in surgical patients for whom infection at the operative site would present serious risk (e.g. , during coronary artery bypass surgery). Although Benaxona for Injection, USP has been shown to have been as effective as cefazolin in the prevention of infection following coronary artery bypass surgery, no placebo-controlled trials have been conducted to evaluate any cephalosporin antibiotic in the prevention of infection following coronary artery bypass surgery.

When administered prior to surgical procedures for which it is indicated, a single 1 gm dose of Benaxona for Injection, USP provides protection from most infections due to susceptible organisms throughout the course of the procedure.

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CONTRAINDICATIONS

Hypersensitivity

Benaxona for injection is contraindicated in patients with known hypersensitivity to Benaxona, any of its excipients or to any other cephalosporin. Patients with previous hypersensitivity reactions to penicillin and other beta lactam antibacterial agents may be at greater risk of hypersensitivity to Benaxona (see WARNINGS – Hypersensitivity).

Neonates

Premature neonates: Benaxona for injection is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age).

Hyperbilirubinemic neonates: Hyperbilirubinemic neonates should not be treated with Benaxona for injection. Benaxona can displace bilirubin from its binding to serum albumin, leading to a risk of bilirubin encephalopathy in these patients.

Neonates Requiring Calcium Containing IV Solutions

Benaxona for injection is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CLINICAL PHARMACOLOGY, WARNINGS and DOSAGE AND ADMINISTRATION ).

Cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Benaxona for injection and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Benaxona for injection and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. There have been no similar reports in patients other than neonates.

Lidocaine

Intravenous administration of Benaxona solutions containing lidocaine is contraindicated. When lidocaine solution is used as a solvent with Benaxona for intramuscular injection, exclude all contraindications to lidocaine. Refer to the prescribing information of lidocaine.

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WARNINGS

Hypersensitivity Reactions

Before therapy with Benaxona for injection is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. This product should be given cautiously to penicillin and other beta-lactam agent-sensitive patients. Antibacterial drugs should be administered with caution to any patient who has demonstrated some form of allergy, particularly to drugs. Serious acute hypersensitivity reactions may require the use of subcutaneous epinephrine and other emergency measures.

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with Benaxona must be discontinued immediately and adequate emergency measures must be initiated.

Interaction with Calcium-Containing Products

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Benaxona for injection vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Benaxona for injection is mixed with calcium-containing solutions in the same IV administration line. Benaxona for injection must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Benaxona for injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ).

Clostridium difficile - Associated Diarrhea

Clostridium difficile associated diarrhea has been reported with use of nearly all antibacterial agents, including Benaxona for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Hemolytic Anemia

An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials including Benaxona for injection. Severe cases of hemolytic anemia, including fatalities, have been reported during treatment in both adults and children. If a patient develops anemia while on Benaxona, the diagnosis of a cephalosporin associated anemia should be considered and Benaxona stopped until the etiology is determined.

PRECAUTIONS

Development of Drug-resistant Bacteria

Prescribing Benaxona for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of Benaxona for injection may result in overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Patients with Renal or Hepatic Impairment

Benaxona is excreted via both biliary and renal excretion. Therefore, patients with renal failure normally require no adjustment in dosage when usual doses of Benaxona for injection are administered.

Dosage adjustments should not be necessary in patients with hepatic dysfunction; however, in patients with both hepatic dysfunction and significant renal disease, caution should be exercised and the Benaxona for injection dosage should not exceed 2 gm daily.

Benaxona is not removed by peritoneal- or hemodialysis. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised.

Effect on Prothrombin Time

Alterations in prothrombin times have occurred in patients treated with Benaxona for injection. Monitor prothrombin time during Benaxona for injection treatment in patients with impaired vitamin K synthesis or low vitamin K stores (eg, chronic hepatic disease and malnutrition). Vitamin K administration (10 mg weekly) may be necessary if the prothrombin time is prolonged before or during therapy.

Concomitant use of Benaxona with Vitamin K antagonists may increase the risk of bleeding. Coagulation parameters should be monitored frequently, and the dose of the anticoagulant adjusted accordingly, both during and after treatment with Benaxona (see ADVERSE REACTIONS ).

Gallbladder Pseudolithiasis

Ceftriaxone-calcium precipitates in the gallbladder have been observed in patients receiving Benaxona for injection. These precipitates appear on sonography as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of gallbladder disease. The condition appears to be reversible upon discontinuation of Benaxona sodium and institution of conservative management. Discontinue Benaxona sodium in patients who develop signs and symptoms suggestive of gallbladder disease and/or the sonographic findings described above.

Urolithiasis and Post-Renal Acute Renal Failure

Ceftriaxone-calcium precipitates in the urinary tract have been observed in patients receiving Benaxona for injection and may be detected as sonographic abnormalities. The probability of such precipitates appears to be greatest in pediatric patients. Patients may be asymptomatic or may develop symptoms of urolithiasis, and ureteral obstruction and post-renal acute renal failure. The condition appears to be reversible upon discontinuation of Benaxona sodium and institution of appropriate management. Ensure adequate hydration in patients receiving Benaxona for injection. Discontinue Benaxona for injection in patients who develop signs and symptoms suggestive of urolithiasis, oliguria or renal failure and/or the sonographic findings described above.

Pancreatitis

Cases of pancreatitis, possibly secondary to biliary obstruction, have been reported in patients treated with Benaxona for injection. Most patients presented with risk factors for biliary stasis and biliary sludge. A cofactor role of Benaxona for injection related biliary precipitation cannot be ruled out.

Information for Patients

  • Patients should be counseled that antibacterial drugs including Benaxona for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., common cold).
  • When Benaxona for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Benaxona for injection or other antibacterial drugs in the future.
  • Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Considering the maximum duration of treatment and the class of the compound, carcinogenicity studies with Benaxona in animals have not been performed. The maximum duration of animal toxicity studies was 6 months.

Mutagenesis: Genetic toxicology tests included the Ames test, a micronucleus test and a test for chromosomal aberrations in human lymphocytes cultured in vitro with Benaxona. Benaxona showed no potential for mutagenic activity in these studies.

Impairment of Fertility: Benaxona produced no impairment of fertility when given intravenously to rats at daily doses up to 586 mg/kg/day, approximately 20 times the recommended clinical dose of 2 gm/day.

Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproductive studies have been performed in mice and rats at doses up to 20 times the usual human dose and have no evidence of embryotoxicity, fetotoxicity or teratogenicity. In primates, no embryotoxicity or teratogenicity was demonstrated at a dose approximately 3 times the human dose.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects: In rats, in the Segment I and Segment III (perinatal and postnatal) studies with intravenously administered Benaxona, no adverse effects were noted on various reproductive parameters during gestation and lactation, including postnatal growth, functional behavior and reproductive ability of the offspring, at doses of 586 mg/kg/day or less.

Nursing Mothers

Low concentrations of Benaxona are excreted in human milk. Caution should be exercised when Benaxona for injection is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Benaxona for injection in neonates, infants and pediatric patients have been established for the dosages described in the DOSAGE AND ADMINISTRATION section. In vitro studies have shown that Benaxona, like some other cephalosporins, can displace bilirubin from serum albumin. Benaxona for injection should not be administered to hyperbilirubinemic neonates, especially prematures.

Geriatric Use

Of the total number of subjects in clinical studies of Benaxona for injection, 32% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of Benaxona were only minimally altered in geriatric patients compared to healthy adult subjects and dosage adjustments are not necessary for geriatric patients with Benaxona dosages up to 2 grams per day provided there is no severe renal and hepatic impairment. (see CLINICAL PHARMACOLOGY ).

Influence on Diagnostic Tests

In patients treated with Benaxona for injection the Coombs' test may become positive. Benaxona for injection, like other antibacterial drugs, may result in positive test results for galactosemia.

Nonenzymatic methods for the glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with Benaxona for injection should be done enzymatically.

The presence of Benaxona may falsely lower estimated blood glucose values obtained with some blood glucose monitoring systems. Please refer to instructions for use for each system. Alternative testing methods should be used if necessary.

ADVERSE REACTIONS

Benaxona for injection is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to Benaxona for injection therapy or of uncertain etiology, were observed:

LOCAL REACTIONS - pain, induration and tenderness was 1% overall. Phlebitis was reported in <1% after IV administration. The incidence of warmth, tightness or induration was 17% after IM administration of 350 mg/mL and 5% (1/20) after IM administration of 250 mg/mL.

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS-injection site pain (0.6%).

HYPERSENSITIVITY - rash (1.7%). Less frequently reported (<1%) were pruritus, fever or chills.

INFECTIONS AND INFESTATIONS - genital fungal infection (0.1%).

HEMATOLOGIC - eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%). Less frequently reported (<1%) were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.

BLOOD AND LYMPHATIC DISORDERS - granulocytopenia (0.9%), coagulopathy (0.4%).

GASTROINTESTINAL - diarrhea /loose stools (2.7%). Less frequently reported (<1%) were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS ).

HEPATIC - elevations of aspartate aminotransferase (AST) (3.1%) or alanine aminotransferase (ALT) (3.3%). Less frequently reported (<1%) were elevations of alkaline phosphatase and bilirubin.

RENAL - elevations of the BUN (1.2%). Less frequently reported (<1%) were elevations of creatinine and the presence of casts in the urine.

CENTRAL NERVOUS SYSTEM - headache or dizziness were reported occasionally (<1%).

GENITOURINARY - moniliasis or vaginitis were reported occasionally (<1%).

MISCELLANEOUS - diaphoresis and flushing were reported occasionally (<1%).

INVESTIGATIONS - blood creatinine increased (0.6%).

Other rarely observed adverse reactions (<0.1%) include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and serum sickness.

Postmarketing Experience

In addition to the adverse reactions reported during clinical trials, the following adverse experiences have been reported during clinical practice in patients treated with Benaxona for injection. Data are generally insufficient to allow an estimate of incidence or to establish causation.

A small number of cases of fatal outcomes in which a crystalline material was observed in the lungs and kidneys at autopsy have been reported in neonates receiving Benaxona for injection and calcium-containing fluids. In some of these cases, the same intravenous infusion line was used for both Benaxona for injection and calcium-containing fluids and in some a precipitate was observed in the intravenous infusion line. At least one fatality has been reported in a neonate in whom Benaxona for injection and calcium-containing fluids were administered at different time points via different intravenous lines; no crystalline material was observed at autopsy in this neonate. There have been no similar reports in patients other than neonates.

GASTROINTESTINAL - pancreatitis, stomatitis and glossitis.

GENITOURINARY - oliguria, ureteric obstruction, post-renal acute renal failure.

DERMATOLOGIC - exanthema, allergic dermatitis, urticaria, edema; acute generalized exanthematous pustulosis (AGEP) and isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome or Lyell's syndrome/toxic epidermal necrolysis) have been reported.

HEMATOLOGICAL CHANGES: Isolated cases of agranulocytosis (< 500/mm3) have been reported, most of them after 10 days of treatment and following total doses of 20 g or more.

NERVOUS SYSTEM DISORDERS: convulsion.

OTHER, Adverse Reactions: symptomatic precipitation of Benaxona calcium salt in the gallbladder, kernicterus, oliguria, and anaphylactic or anaphylactoid reactions.

Cephalosporin Class Adverse Reactions

In addition to the adverse reactions listed above which have been observed in patients treated with Benaxona, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics:

Adverse Reactions: Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including hepatitis cholestasis, aplastic anemia, hemorrhage, and superinfection.

Altered Laboratory Tests: Positive direct Coombs' test, false-positive test for urinary glucose, and elevated LDH (see PRECAUTIONS ).

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced (see DOSAGE AND ADMINISTRATION ). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

OVERDOSAGE

In the case of overdosage, drug concentration would not be reduced by hemodialysis or peritoneal dialysis. There is no specific antidote. Treatment of overdosage should be symptomatic.

DOSAGE AND ADMINISTRATION

Benaxona for injection may be administered intravenously or intramuscularly.

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Benaxona for injection vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when Benaxona for injection is mixed with calcium-containing solutions in the same IV administration line. Benaxona for injection must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Benaxona for injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS ).

There have been no reports of an interaction between Benaxona and oral calcium-containing products or interaction between intramuscular Benaxona and calcium-containing products (IV or oral).

NEONATES: Hyperbilirubinemic neonates, especially prematures, should not be treated with Benaxona for injection. Benaxona for injection is contraindicated in premature neonates (see CONTRAINDICATIONS ).

Benaxona for injection is contraindicated in neonates (≤ 28 days) if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone- calcium (see CONTRAINDICATIONS ).

Intravenous doses should be given over 60 minutes in neonates to reduce the risk of bilirubin encephalopathy.

PEDIATRIC PATIENTS: For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses every 12 hours). The total daily dose should not exceed 2 grams.

For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE ).

For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.

In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

ADULTS: The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. The total daily dose should not exceed 4 grams.

If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because Benaxona sodium has no activity against this organism.

For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

Generally, Benaxona for injection therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

No dosage adjustment is necessary for patients with impairment of renal or hepatic function (see PRECAUTIONS ).

The dosages recommended for adults require no modification in elderly patients, up to 2 gm per day, provided there is no severe renal and hepatic impairment (see PRECAUTIONS ).

DIRECTIONS FOR USE

Intramuscular Administration

Reconstitute Benaxona for injection with the appropriate diluent (see COMPATIBILITY AND STABILITY ).

Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose.

After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of Benaxona according to the amount of diluent indicated below. If required, more dilute solutions could be utilized. A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents.

As with all intramuscular preparations, Benaxona for injection should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.


Vial Dosage Size


Amount of Diluent to be Added


250 mg/mL


350 mg/mL


250 mg


0.9 mL


-


500 mg


1.8 mL


1 mL


1 gm


3.6 mL


2.1 mL


2 gm


7.2 mL


4.2 mL


Intravenous Administration

Benaxona for injection should be administered intravenously by infusion over a period of 30 minutes, except in neonates where administration over 60 minutes is recommended to reduce the risk of bilirubin encephalopathy. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials or "piggyback" bottles with an appropriate IV diluent (see COMPATIBILITY AND STABILITY ).


Vial Dosage Size


Amount of Diluent to be Added


250 mg


2.4 mL


500 mg


4.8 mL


1 gm


9.6 mL


2 gm


19.2 mL


After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of Benaxona. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.


Piggyback Bottle Dosage Size


Amount of Diluent to be Added


1 gm


10 mL


2 gm


20 mL


After reconstitution, further dilute to 50 mL or 100 mL volumes with the appropriate IV diluent.

COMPATIBILITY AND STABILITY

Do not use diluents containing calcium, such as Ringer's solution or Hartmann's solution, to reconstitute Benaxona for injection or to further dilute a reconstituted vial for IV administration. Particulate formation can result.

Benaxona has been shown to be compatible with Flagyl® IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with Benaxona 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.

Vancomycin, amsacrine, aminoglycosides, and fluconazole are incompatible with Benaxona in admixtures. When any of these drugs are to be administered concomitantly with Benaxona by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.

Benaxona for injection solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS ).

Benaxona for injection sterile powder should be stored at 20° to 25°C (68° to 77°F) and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

Benaxona for injection intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods:


Storage


Diluent


Concentration


Room Temp.


Refrigerated


mg/mL


(25°C)


(4°C)


Sterile Water for Injection


100


2 days


10 days


250, 350


24 hours


3 days


0.9% Sodium Chloride


100


2 days


10 days


Solution


250, 350


24 hours


3 days


5% Dextrose Solution


100


2 days


10 days


250, 350


24 hours


3 days


Bacteriostatic Water + 0.9%


100


24 hours


10 days


Benzyl Alcohol


250, 350


24 hours


3 days


1% Lidocaine Solution


100


24 hours


10 days


(without epinephrine)


250, 350


24 hours


3 days


Benaxona for injection intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:



Diluent


Storage


Room Temp.

(25°C)


Refrigerated

(4°C)


Sterile Water


2 days


10 days


0.9% Sodium Chloride Solution


2 days


10 days


5% Dextrose Solution


2 days


10 days


10% Dextrose Solution


2 days


10 days


5% Dextrose + 0.9% Sodium Chloride SolutionData available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.


2 days


Incompatible


5% Dextrose + 0.45% Sodium Chloride Solution


2 days


Incompatible


Similarly, Benaxona for injection intravenous solutions, at concentrations of 100 mg/mL, remain stable in the IV piggyback glass containers for the above specified time periods.

The following intravenous Benaxona for injection solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).

After the indicated stability time periods, unused portions of solutions should be discarded.

NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.

Benaxona for injection reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.

Frozen solutions of Benaxona for injection should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

ANIMAL PHARMACOLOGY

Concretions consisting of the precipitated calcium salt of Benaxona have been found in the gallbladder bile of dogs and baboons treated with Benaxona.

These appeared as a gritty sediment in dogs that received 100 mg/kg/day for 4 weeks. A similar phenomenon has been observed in baboons but only after a protracted dosing period (6 months) at higher dose levels (335 mg/kg/day or more). The likelihood of this occurrence in humans is considered to be low, since Benaxona has a greater plasma half-life in humans, the calcium salt of Benaxona is more soluble in human gallbladder bile and the calcium content of human gallbladder bile is relatively low.

HOW SUPPLIED

Benaxona for Injection, USP is supplied as a sterile crystalline powder in glass vials and piggyback bottles. The following packages are available:


Unit of Sale


Strength


Each


NDC 60505-0750-0

Carton containing 1


250 mg


NDC 60505-0750-0

Vial


NDC 60505-0750-4

Carton containing 10


250 mg


NDC 60505-0750-1

Vial


NDC 60505-0751-0

Carton containing 1


500 mg


NDC 60505-0751-0

Vial


NDC 60505-0751-4

Carton containing 10


500 mg


NDC 60505-0751-1

Vial


NDC 60505-0752-0

Carton containing 1


1 g


NDC 60505-0752-0

Vial


NDC 60505-0752-4

Carton containing 10


1 g


NDC 60505-0752-3

Vial


NDC 60505-0753-0

Carton containing 1


2 g


NDC 60505-0753-0

Vial


NDC 60505-0753-4

Carton containing 10


2 g


NDC 60505-0753-3

Vial


Piggyback bottles containing


Unit of Sale


Strength


Each


NDC 60505-6087-1

Carton containing 1


1 gram


NDC 60505-6087-1

Vial


NDC 60505-6088-1

Carton containing 1


2 grams


NDC 60505-6088-1

Vial


Storage Prior to Reconstitution: Store at 20° to 25°C (68° to 77°F). Protect from light.

CLINICAL STUDIES

Clinical Trials in Pediatric Patients With Acute Bacterial Otitis Media: In two adequate and well-controlled U.S. clinical trials a single IM dose of Benaxona was compared with a 10 day course of oral antibiotic in pediatric patients between the ages of 3 months and 6 years. The clinical cure rates and statistical outcome appear in the table below:


Clinical Efficacy in Evaluable Population


Study Day


Benaxona

Single Dose


Comparator –

10 Days of

Oral Therapy


95%

Confidence

Interval


Statistical

Outcome


Study 1 – U.S.


amoxicillin/

clavulanate


14


74% (220/296)


82% (247/302)


(-14.4%, -0.5%)


Benaxona is

lower than


28


58% (167/288)


67% (200/297)


(-17.5%, -1.2%)


control at study

day 14 and 28.


Study 2 – U.S.5


TMP-SMZ



14


54% (113/210)


60% (124/206)


(-16.4%, 3.6%)


Benaxona is

equivalent to


28


35% (73/206)


45% (93/205)


(-19.9%, 0.0%)


control at study

day 14 and 28.


An open-label bacteriologic study of Benaxona without a comparator enrolled 108 pediatric patients, 79 of whom had positive baseline cultures for one or more of the common pathogens. The results of this study are tabulated as follows:

Week 2 and 4 Bacteriologic Eradication Rates in the Per Protocol Analysis in the Roche Bacteriologic Study by pathogen:




Study Day

13 to 15


Study Day

30+2


Organism


No.

Analyzed


No.

Erad. (%)


No.

Analyzed


No.

Erad. (%)


Streptococcus pneumoniae


38


32 (84)


35


25 (71)


Haemophilus influenzae


33


28 (85)


31


22 (71)


Moraxella catarrhalis


15


12 (80)


15


9 (60)

REFERENCES

  • Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
  • Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
  • Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
  • Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eight Edition. CLSI document M11-A8, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
  • Barnett ED, Teele DW, Klein JO, et al. Comparison of Benaxona and Trimethoprim-Sulfamethoxazole for Acute Otitis Media. Pediatrics. Vol. 99, No. 1, January 1997.

Flagyl® is a registered trademark of G.D. Searle & Co.


Mfg. by: Mfg. for:

Hospira Healthcare India Pvt. Ltd. Apotex Corp.

Irungattukottai - 602 105, India Weston, FL 33326

DATE OF REVISION: February 2016

948026417

NDC 60505-0750-0

10 mL Vial

Benaxona

For Injection USP

250 mg*

Single Use Vial

For I.M. or I.V. Use

Rx Only

APOTEX CORP.

Benaxona pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Benaxona available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Benaxona destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Benaxona Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Benaxona pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."CEFTRIAXONE SODIUM INJECTION, POWDER, FOR SOLUTION [SANDOZ INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."CEFTRIAXONE SODIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "ceftriaxone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Benaxona?

Depending on the reaction of the Benaxona after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Benaxona not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Benaxona addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Benaxona, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Benaxona consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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