CEFTRIAXONE SOD
DESCRIPTION:
Monocef is a sterile, semisynthetic, broad- spectrum cephalosporin antibiotic
for intravenous or intramuscular administration. Ceftriaxone sodium is (6R,7R)-
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, 7(squared)-(Z)-(O-methyloxime), disodium salt,
sesquaterhydrate.
The chemical formula of ceftriaxone sodium is C18 H16 N8 Na2 O7 S3 3.5 H2O. It
has a calculated molecular weight of 661.59.
Monocef 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
Monocef solutions ranges from light yellow to amber, depending on the length of
storage, concentration and diluent used.
Monocef contains approximately 83 mg (3.6 mEq) of sodium per gram of
ceftriaxone activity.
ACTIONS/CLINICAL PHARMACOLOGY:
Average plasma concentrations of ceftriaxone 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.
TABLE 1 Ceftriaxone Plasma Concentrations After Single Dose Administration
Dose/Route Average Plasma Concentrations (mcg/mL)
0.5 1 2 4 6 8 12 16 24
hr hr hr hr hr hr hr hr hr
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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
*IV doses were infused at a constant rate over 30 minutes.
ND = Not determined.
Ceftriaxone was completely absorbed following IM administration with mean
maximum plasma concentrations occurring between 2 and 3 hours postdosing.
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 ceftriaxone above single dose values.
Ceftriaxone concentrations in urine are high, as shown in Table 2.
TABLE 2 Urinary Concentrations of Ceftriaxone After Single Dose Administration
Dose/Route Average Urinary Concentrations (mcg/mL)
0-2 hr 2-4 hr 4-8 hr 8-12 hr 12-24 hr 24-48 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
*ND = Not determined.
Thirty-three percent to 67% of a ceftriaxone 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 ceftriaxone, 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. Ceftriaxone 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.
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. Ceftriaxone penetrated the inflamed meninges of infants and
children; CSF concentrations after a 50 mg/kg IV dose and after a 75 mg/kg IV
dose are also shown in Table 3.
TABLE 3 Average Pharmacokinetic Parameters of Ceftriaxone
in Pediatric Patients With Meningitis
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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) 1.3-18.5 1.3-44
Time after dose (hr) 3.7 (+/- 1.6) 3.3 (+/-1.4)
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Compared to that in healthy adult subjects, the pharmacokinetics of ceftriaxone
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 ceftriaxone dosages up to 2 gm per day.
Ceftriaxone was not removed to any significant extent from the plasma by
hemodialysis. In 6 of 26 dialysis patients, the elimination rate of ceftriaxone
was markedly reduced, suggesting that plasma concentrations of ceftriaxone
should be monitored in these patients to determine if dosage adjustments are
necessary.
TABLE 4 Average Pharmacokinetic Parameters of Ceftriaxone in Humans
Subject Elimination Plasma Volume of
Group Half-Life (hr) Clearance (L/hr) Distribution (L)
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Healthy Subjects 5.8-8.7 0.58-1.45 5.8-13.5
Elderly Subjects 8.9 0.83 10.7
(mean age, 70.5 yr)
Patients with renal impairment
Hemodialysis patients 14.7 0.65 13.7
(0-5 mL/min*
Severe (5-15 mL/min) 15.7 0.56 12.5
Moderate (16-30 mL/min) 11.4 0.72 11.8
Mild (31-60 mL/min) 12.4 0.70 13.3
Patients with liver disease 8.8 1.1 13.6
*Creatinine clearance.
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PHARMACOKINETICS IN THE MIDDLE EAR FLUID: In one study, total ceftriaxone
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 ceftriaxone. Mean (+/- SD) ceftriaxone levels in the
middle ear reached a peak of 35 (+/- 12) Mu- g/mL at 24 hours, and remained at
19 (+/- 7) Mu- g/mL at 48 hours. Based on middle ear fluid ceftriaxone
concentrations in the 23 to 25 hour and the 46 to 50 hour sampling time
intervals, a half-life of 25 hours was calculated. Ceftriaxone is highly bound
to plasma proteins. The extent of binding to proteins in the middle ear fluid is
unknown.
MICROBIOLOGY: The bactericidal activity of ceftriaxone results from inhibition
of cell wall synthesis. Ceftriaxone has a high degree of stability in the
presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-
negative and gram-positive bacteria. Ceftriaxone is usually active against the
following microorganisms in vitro and in clinical infections (see INDICATIONS
AND USAGE):
GRAM-NEGATIVE AEROBES:
ACINETOBACTER CALCOACETICUS
ENTEROBACTER AEROGENES
ENTEROBACTER CLOACAE
ESCHERICHIA COLI
HAEMOPHILUS INFLUENZAE (including ampicillin- resistant and beta-lactamase
producing strains)
HAEMOPHILUS PARAINFLUENZAE
KLEBSIELLA OXYTOCA
KLEBSIELLA PNEUMONIAE
MORAXELLA CATARRHALIS (including beta-lactamase producing strains)
MORGANELLA MORGANII
NEISSERIA GONORRHOEAE (including penicillinase- and nonpenicillinase-producing
strains)
NEISSERIA MENINGITIDIS
PROTEUS MIRABILIS
PROTEUS VULGARIS
SERRATIA MARCESCENS
Ceftriaxone is also active against many strains of PSEUDOMONAS AERUGINOSA.
Note: Many strains of the above organisms that are multiply resistant to other
antibiotics, eg, penicillins, cephalosporins and aminoglycosides, are
susceptible to ceftriaxone.
GRAM-POSITIVE AEROBES:
STAPHYLOCOCCUS AUREUS (including penicillinase- producing strains)
STAPHYLOCOCCUS EPIDERMIDIS
STREPTOCOCCUS PNEUMONIAE
STREPTOCOCCUS PYOGENES
VIRIDANS group streptococci
Note: Methicillin-resistant staphylococci are resistant to cephalosporins,
including ceftriaxone. Most strains of Group D streptococci and enterococci, eg,
ENTEROCOCCUS (STREPTOCOCCUS) FAECALIS, are resistant.
ANAEROBES:
BACTEROIDES FRAGILIS
CLOSTRIDIUM species
PEPTOSTREPTOCOCCUS species
Note: Most strains of C. DIFFICILE are resistant.
Ceftriaxone also demonstrates in vitro activity against most strains of the
following microorganisms, although the clinical significance is unknown:
GRAM-NEGATIVE AEROBES:
CITROBACTER DIVERSUS
CITROBACTER FREUNDII
PROVIDENCIA species (including PROVIDENCIA RETTGERI)
SALMONELLA species (including S. TYPHI)
SHIGELLA species
GRAM-POSITIVE AEROBES:
STREPTOCOCCUS AGALACTIAE
ANAEROBES:
BACTEROIDES BIVIUS
BACTEROIDES MELANINOGENICUS
SUSCEPTIBILITY TESTS: DIFFUSION TECHNIQUES: Quantitative methods that require
the measurement of zone diameters give the most precise estimate of the
susceptibility of bacteria to antimicrobial agents. One such standard
procedure(REF.1) which has been recommended for use with disks to test
susceptibility of organisms to ceftriaxone uses a 30-mcg ceftriaxone disk.
Interpretation involves the correlation of the diameters obtained in the disk
test with the minimum inhibitory concentration (MIC) for ceftriaxone.
from the laboratory giving results of the standardized single disk
susceptibility test using a 30-mcg ceftriaxone disk should be interpreted for
ceftriaxone according to the following criteria:
ZONE DIAMETER (MM) INTERPRETATION
(>/=)18 (S) Susceptible
14-17 (MS) Moderately Susceptible
(=)13 (R) Resistant
A report of "Susceptible" indicates that the pathogen is likely to be inhibited
by generally achievable levels. A report of "Moderately Susceptible" suggests
that the organism would be susceptible if high dosage (not to exceed 4 gm per
day) is used or if the infection is confined to tissues and fluids in which high
antimicrobial levels are attained. A report of "Resistant" indicates that
achievable concentrations are unlikely to be inhibitory, and other therapy
should be selected.
Standardized procedures require the use of laboratory control organisms. The 30-
mcg ceftriaxone disk should give the following zone diameters:
ORGANISM ZONE DIAMETER (MM)
STAPHYLOCOCCUS AUREUS ATCC(R) 25923 22-28
ESCHERICHIA COLI ATCC(R) 25922 29-35
PSEUDOMONAS AERUGINOSA ATCC(R) 27853 17-23
DILUTION TECHNIQUES:
Use a standardized dilution method(REF. 2) (broth, agar, microdilution) or
equivalent with ceftriaxone powder. The MIC values obtained should be
interpreted according to the following criteria:
MIC (MCG/ML) INTERPRETATION
(=)16 Susceptible
>16-<64 Moderately Susceptible
(>/=)64 Resistant
As with standard diffusion techniques, dilution methods require the use of
laboratory control organisms. Standard ceftriaxone powder should provide the
following MIC values:
ORGANISM MIC (MCG/ML)
STAPHYLOCOCCUS AUREUS ATCC(R) 29213 1-8
ESCHERICHIA COLI ATCC(R) 25922 0.03-0.12
PSEUDOMONAS AERUGINOSA ATCC(R) 27853 8-32
INDICATIONS AND USAGE:
Monocef 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 Monocef compared to 10 days of oral therapy. In a second study comparable
cure rates were observed between single dose Monocef and the comparator. The
potentially lower clinical cure rate of Monocef 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. Monocef, like
other cephalosporins, has no activity against CHLAMYDIA TRACHOMATIS. Therefore,
when cephalosporins are used in the treatment of patients with pelvic
inflammatory disease and C. 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 C. DIFFICILE
are resistant) or PEPTOSTREPTOCOCCUS species.
MENINGITIS caused by HAEMOPHILUS INFLUENZAE, NEISSERIA MENINGITIDIS or
STREPTOCOCCUS PNEUMONIAE. Monocef 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
Monocef may reduce the incidence of postoperative infections in patients
undergoing surgical procedures classified as contaminated or potentially
contaminated (eg, 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 (eg, during
coronary artery bypass surgery). Although Monocef 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 Monocef provides protection from most infections due to
susceptible organisms throughout the course of the procedure.
Before instituting treatment with Monocef, 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.
CONTRAINDICATIONS:
Monocef is contraindicated in patients with known allergy to the cephalosporin
class of antibiotics.
WARNINGS:
BEFORE THERAPY WITH MONOCEF IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO
DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO
CEPHALOSPORINS, PENICILLINS OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN
CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS 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.
PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH NEARLY ALL ANTIBACTERIAL AGENTS,
INCLUDING CEFTRIAXONE, AND MAY RANGE IN SEVERITY 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 antibacterial agents alters the normal flora of the colon and may
permit overgrowth of clostridia. Studies indicate that a toxin produced by
CLOSTRIDIUM DIFFICILE is one primary cause of "antibiotic-associated colitis."
After the diagnosis of pseudomembranous colitis has been established,
appropriate therapeutic measures should be initiated. Mild cases of
pseudomembranous colitis usually respond to drug discontinuation alone. In
moderate to severe cases, consideration should be given to management with
fluids and electrolytes, protein supplementation and treatment with an
antibacterial drug clinically effective against C. DIFFICILE colitis.
PRECAUTIONS:
GENERAL: Although transient elevations of BUN and serum creatinine have been
observed, at the recommended dosages, the nephrotoxic potential of Monocef is
similar to that of other cephalosporins.
Ceftriaxone is excreted via both biliary and renal excretion (see
ACTIONS/CLINICAL PHARMACOLOGY). Therefore, patients with renal failure normally
require no adjustment in dosage when usual doses of Monocef are administered,
but concentrations of drug in the serum should be monitored periodically. If
evidence of accumulation exists, dosage should be decreased accordingly.
Dosage adjustments should not be necessary in patients with hepatic dysfunction;
however, in patients with both hepatic dysfunction and significant renal
disease, Monocef dosage should not exceed 2 gm daily without close monitoring
of serum concentrations.
Alterations in prothrombin times have occurred rarely in patients treated with
Monocef. Patients with impaired vitamin K synthesis or low vitamin K stores
(eg, chronic hepatic disease and malnutrition) may require monitoring of
prothrombin time during Monocef treatment. Vitamin K administration (10 mg
weekly) may be necessary if the prothrombin time is prolonged before or during
therapy.
Prolonged use of Monocef may result in overgrowth of nonsusceptible organisms.
Careful observation of the patient is essential. If superinfection occurs during
therapy, appropriate measures should be taken.
Monocef should be prescribed with caution in individuals with a history of
gastrointestinal disease, especially colitis.
THERE HAVE BEEN REPORTS OF SONOGRAPHIC ABNORMALITIES IN THE GALLBLADDER OF
PATIENTS TREATED WITH MONOCEF; SOME OF THESE PATIENTS ALSO HAD SYMPTOMS OF
GALLBLADDER DISEASE. These abnormalities 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 chemical nature of the
sonographically detected material has been determined to be predominantly a
ceftriaxone- calcium salt. THE CONDITION APPEARS TO BE TRANSIENT AND REVERSIBLE
UPON DISCONTINUATION OF MONOCEF AND INSTITUTION OF CONSERVATIVE MANAGEMENT.
Therefore, Monocef should be discontinued in patients who develop signs and
symptoms suggestive of gallbladder disease and/or the sonographic findings
described above.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: CARCINOGENESIS:
Considering the maximum duration of treatment and the class of the compound,
carcinogenicity studies with ceftriaxone 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 ceftriaxone. Ceftriaxone showed no potential for mutagenic activity
in these studies.
IMPAIRMENT OF FERTILITY: Ceftriaxone 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 (fertility and general
reproduction) and Segment III (perinatal and postnatal) studies with
intravenously administered ceftriaxone, 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 ceftriaxone are excreted in human milk.
Caution should be exercised when Monocef is administered to a nursing woman.
PEDIATRIC USE: Safety and effectiveness of Monocef in neonates, infants and
children have been established for the dosages described in the (DOSAGE AND
ADMINISTRATION section. In vitro studies have shown that ceftriaxone, like some
other cephalosporins, can displace bilirubin from serum albumin. Monocef should
not be administered to hyperbilirubinemic neonates, especially prematures.
ADVERSE REACTIONS:
Monocef is generally well tolerated. In clinical trials, the following adverse
reactions, which were considered to be related to Monocef 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 injection site
reaction was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after
IM administration of 250 mg/mL.
HYPERSENSITIVITY--rash (1.7%). Less frequently reported (<1%) were pruritus,
fever or chills.
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.
GASTROINTESTINAL--diarrhea (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 SGOT (3.1%) or SGPT (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%).
Other rarely observed adverse reactions (<0.1%) include leukocytosis,
lymphocytosis, monocytosis, basophilia, a decrease in the prothrombin time,
jaundice, gallbladder sludge, glycosuria, hematuria, anaphylaxis, bronchospasm,
serum sickness, abdominal pain, colitis, flatulence, dyspepsia, palpitations and
epistaxis.
DOSAGE AND ADMINISTRATION:
Monocef may be administered intravenously or intramuscularly.
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 C. TRACHOMATIS is a suspected pathogen, appropriate antichlamydial coverage
should be added, because ceftriaxone 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.
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 twice a day). 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.
Generally, Monocef 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; however, blood levels should be monitored in patients with
severe renal impairment (eg, dialysis patients) and in patients with both renal
and hepatic dysfunctions.
DIRECTIONS FOR USE: INTRAMUSCULAR ADMINISTRATION: Reconstitute Monocef powder
with the appropriate diluent (see COMPATIBILITY AND STABILITY section).
After reconstitution, each 1 mL of solution contains approximately 250 mg or 350
mg equivalent of ceftriaxone 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, Monocef should be
injected well within the body of a relatively large muscle; aspiration helps to
avoid unintentional injection into a blood vessel.
AMOUNT OF DILUENT
VIAL DOSAGE SIZE TO BE ADDED
250 MG/ML 350 MG/ML
250 mg 0.9 mL -
500 mg 1.8 mL 1.0 mL
1 gm 3.6 mL 2.1 mL
2 gm 7.2 mL 4.2 mL
INTRAMUSCULAR CONVENIENCE KIT: For the 500 mg vial, withdraw 1 mL of diluent,
discard the remainder. Inject diluent into vial, shake vial thoroughly to form
solution. Withdraw entire contents of vial into syringe to equal approximately
1.4 mL.
For 1 gm vial, withdraw entire contents of diluent (2.1 mL). Inject diluent into
vial, shake vial thoroughly to form solution. Withdraw entire contents of vial
into syringe to equal approximately 2.8 mL.
INTRAVENOUS ADMINISTRATION: Monocef should be administered intravenously by
infusion over a period of 30 minutes. 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 section).
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 ceftriaxone. 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: Monocef sterile powder should be stored at room
temperature--77 deg F (25 deg C)--or below 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.
Monocef INTRAMUSCULAR solutions remain stable (loss of potency less than 10%)
for the following time periods:
Concentration Storage
Diluent mg/mL Room Temp, Refrigerated
(25 deg C) (40 deg C)
----------------------------------------------------------------------------------------------------------------------------------------------------------
Sterile Water for 100 3 days 10 days
Injection 250, 350 24 hours 3 days
0.9% Sodium 100 3 days 10 days
Chloride Solution 250, 350 24 hours 3 days
5% Dextrose 100 3 days 10 days
Solution 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
Monocef 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:
Storage
Diluent Room Temp, Refrigerated
25 deg C) (40 deg C)
Sterile Water 3 days 10 days
0.9% Sodium Chloride Solution 3 days 10 days
5% Dextrose Solution 3 days 10 days
10% Dextrose Solution 3 days 10 days
5% Dextrose + 0.9% Sodium Chloride Solution(*) 3 days Incompatible
5% Dextrose + 0.45% Sodium Chloride Solution 3 days Incompatible
-------------------------------------------------------------------------------------------------------------------------------------------------------------
*Data available for 10 to 40 mg/mL concentrations in this diluent in PVC
containers only.
Similarly, Monocef 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 Monocef solutions are stable at room temperature (25
deg C) for 24 hours, at concentrations between 10 mg/mL and 40mg/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.
Monocef 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 deg C) in PVC or polyolefin containers, remains stable for 26 weeks.
Frozen solutions should be thawed at room temperature before use. After thawing,
unused portions should be discarded. DO NOT REFREEZE.
Monocef 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.
ANIMAL PHARMACOLOGY:
Concretions consisting of the precipitated calcium salt of ceftriaxone have been
found in the gallbladder bile of dogs and baboons treated with ceftriaxone.
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 ceftriaxone has a greater plasma half-life in humans, the calcium salt of
ceftriaxone is more soluble in human gallbladder bile and the calcium content of
human gallbladder bile is relatively low.
HOW SUPPLIED:
Monocef is supplied as a sterile crystalline powder in glass vials and
piggyback bottles. The following packages are available:
Vials containing 250 mg equivalent of ceftriaxone. Box of 1 (NDC 0004-1962-02)
and box of 10 (NDC 0004-1962-01).
Vials containing 500 mg equivalent of ceftriaxone. Box of 1 (NDC 0004-1963-02)
and box of 10 (NDC 0004-1963-01).
Vials containing 1 gm equivalent of ceftriaxone. Box of 1 (NDC 0004-1964-04) and
box of 10 (NDC 0004-1964-01).
Piggyback bottles containing 1 gm equivalent of ceftriaxone. Box of 1 (NDC 0004-
1964-02).
Vials containing 2 gm equivalent of ceftriaxone. Box of 10 (NDC 0004-1965-01).
Piggyback bottles containing 2 gm equivalent of ceftriaxone. Box of 1 (NDC 0004-
1965-02).
Bulk pharmacy containers, containing 10 gm equivalent of ceftriaxone. Box of 1
(NDC 0004-1971-01). NOT FOR DIRECT ADMINISTRATION.
Monocef is also supplied in an Intramuscular Convenience Kit, available in two
strengths, consisting of a vial of ceftriaxone sodium as a sterile crystalline
powder and a vial of Xylocaine(R)-MPF 1% (lidocaine HCl Injection, USP).
The following strengths are available:
Kit containing 1 vial of 500 mg equivalent of ceftriaxone, plus 1 vial of 2.1 mL
Xylocaine (NDC 0004-2014-92).
Kit containing 1 vial of 1 gm equivalent of ceftriaxone, plus 1 vial of 2.1 mL
Xylocaine (NDC 0004-2013-92).
Xylocaine(R)-MPF 1% (lidocaine HCl Injection, USP) is manufactured for Roche
Laboratories Inc. by Astra USA, Inc., Westborough, MA 01581.
Monocef is also supplied as a sterile crystalline powder in ADD-Vantage(R)(*)
Vials as follows:
ADD-Vantage Vials containing 1 gm equivalent of ceftriaxone. Box of 10 (NDC
0004-1964-05).
ADD-Vantage Vials containing 2 gm equivalent of ceftriaxone. Box of 10 (NDC
0004-1965-05).
Monocef (ceftriaxone sodium injection), also supplied premixed as a frozen,
iso-osmotic, sterile, nonpyrogenic solution of ceftriaxone sodium in 50 mL
single dose Galaxy(R)** containers (PL 2040 plastic), is manufactured for Roche
Laboratories Inc., by Baxter Healthcare Corporation, Deerfield, Illinois 60015.
The following strengths are available:
1 gm equivalent of ceftriaxone, iso-osmotic with approximately 1.9 gm Dextrose
Hydrous, USP, added (NDC 0004-2002-78).
2 gm equivalent of ceftriaxone, iso-osmotic with approximately 1.2 gm Dextrose
Hydrous, USP, added (NDC 0004-2003-78).
NOTE: Store Monocef in the frozen state at or below -20 deg C/-4 deg F.
*Registered trademark of Abbott Laboratories, Inc. ** Registered trademark of
Baxter International Inc. Revised: January 1998
CLINICAL STUDIES:
CLINICAL TRIALS IN PEDIATRIC PATIENTS WITH ACUTE BACTERIAL OTITIS MEDIA: In two
adequate and well controlled US clinical trials a single IM dose of ceftriaxone
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 Ceftriaxone Comparator--10 days 95% Confidence Statistical
Day Single Dose of Oral Therapy Interval Outcome
------------------------------------------------------------------------------------------------------------------------------------------------------
Study 1--US amoxicillin/clavulanate
14 74% (220/296) 82% (247/302) (-14.4%, -0.5%) Ceftriaxone
is lower
than
control at
study day
28 58% (167/288) 67% (200/297) (-17.5%, -1.2%) 14 and 28.
-------------------------------------------------------------------------------------------------------------------------------------------------------
Study 2--US TMP-SMZ
(REF.3)
14 54% (113/210) 60% (124/206) (-16.4%, 3.6%) Ceftriaxone
is
equivalent
to control
at
study day
28 35% (73/206) 45% (93/205) (-19.9%, 0.0%) 14 and 28.
An open-label bacteriologic study of ceftriaxone 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 Study Day
13-15 30+2
Organism No. Analyzed No. Erad. (%) No. Analyzed No. Erad. (%)
S. PNEUMONIAE 38 32 (84) 35 25 (71)
H. INFLUENZAE 33 28 (85) 31 22 (71)
M. CATARRHALIS 15 12 (80) 15 9 (60)