Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2196
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TIMENTIN (Injection, Powder, For Solution)
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TIMENTIN should be administered by intravenous infusion
(30 min.).<br/>Adults: The usual recommended dosage for systemic and urinary
tract infections for average (60 kg) adults is 3.1 grams
of TIMENTIN (3.1-gram vial containing 3 grams ticarcillin and
100 mg clavulanic acid) given every 4 to 6 hours. For gynecologic
infections, TIMENTIN should be administered as follows: Moderate infections,
200 mg/kg/day in divided doses every 6 hours, and for severe
infections, 300 mg/kg/day in divided doses every 4 hours.
For patients weighing less than 60 kg, the recommended dosage
is 200 to 300 mg/kg/day, based on ticarcillin content, given
in divided doses every 4 to 6 hours.<br/>Pediatric Patients (���3 months):<br/>For patients<60 kg: In patients<60 kg, TIMENTIN is dosed at
50 mg/kg/dose based on the ticarcillin component. TIMENTIN should
be administered as follows: Mild to moderate infections, 200 mg/kg/day
in divided doses every 6 hours; for severe infections, 300 mg/kg/day
in divided doses every 4 hours.<br/>For patients���60 kg: For mild to moderate infections, 3.1 grams
of TIMENTIN (3 grams of ticarcillin and 100 mg of clavulanic
acid) administered every 6 hours; for severe infections, 3.1 grams
every 4 hours.<br/>Renal Impairment: For infections complicated by renal insufficiency, an initial loading dose of 3.1 grams should
be followed by doses based on creatinine clearance and type of dialysis
as indicated below: Dosage for any individual patient must take into
consideration the site and severity of infection, the susceptibility
of the organisms causing infection, and the status of the patient's
host defense mechanisms. The duration of therapy
depends upon the severity of infection. Generally, TIMENTIN should
be continued for at least 2 days after the signs and symptoms
of infection have disappeared. The usual duration is 10 to 14 days;
however, in difficult and complicated infections, more prolonged therapy
may be required. Frequent bacteriologic and
clinical appraisals are necessary during therapy of chronic urinary
tract infection and may be required for several months after therapy
has been completed. Persistent infections may require treatment for
several weeks, and doses smaller than those indicated above should
not be used. In certain infections, involving
abscess formation, appropriate surgical drainage should be performed
in conjunction with antimicrobial therapy. INTRAVENOUS
ADMINISTRATION DIRECTIONS FOR USE 3.1-gram Vials The 3.1-gram vial
should be reconstituted by adding approximately 13 mL of Sterile
Water for Injection, USP, or Sodium Chloride Injection, USP, and shaking
well. When dissolved, the concentration of ticarcillin will be approximately
200 mg/mL with a corresponding concentration of 6.7 mg/mL
for clavulanic acid. Conversely, each 5.0 mL of the 3.1-gram
dose reconstituted with approximately 13 mL of diluent will contain
approximately 1 gram of ticarcillin and 33 mg of clavulanic
acid.<br/>Intravenous Infusion: The dissolved drug should be further diluted to
desired volume using the recommended solution listed in the COMPATIBILITY
AND STABILITY Section (STABILITY PERIOD) to a concentration between
10 mg/mL to 100 mg/mL. The solution of reconstituted drug
may then be administered over a period of 30 minutes by direct
infusionor through a Y-type intravenous infusion set. If this method
of administration is used, it is advisable to discontinue temporarily
the administration of any other solutions during the infusion of TIMENTIN.<br/>Stability: For I.V. solutions, see STABILITY PERIOD below. When TIMENTIN is given in combination with another antimicrobial,
such as an aminoglycoside, each drug should be given separately in
accordance with the recommended dosage and routes of administration
for each drug. After reconstitution and prior
to administration, TIMENTIN, as with other parenteral drugs, should
be inspected visually for particulate matter. If this condition is
evident, the solution should be discarded. The
color of reconstituted solutions of TIMENTIN normally ranges from
light to dark yellow, depending on concentration, duration, and temperature
of storage while maintaining label claim characteristics. COMPATIBILITY AND STABILITY 3.1-gram Vials (Dilutions derived
from a stock solution of 200 mg/mL) The concentrated stock solution at 200 mg/mL is
stable for up to 6 hours at room temperature 21��to 24��C
(70��to 75��F) or up to 72 hours under refrigeration
4��C (40��F). If the concentrated stock
solution (200 mg/mL) is held for up to 6 hours at room temperature
21��to 24��C (70��to 75��F) or up to 72 hours
under refrigeration 4��C (40��F) and further diluted to a
concentration between 10 mg/mL and 100 mg/mL with any of
the diluents listed below, then the following stability periods apply. If the concentrated stock solution (200 mg/mL)
is stored for up to 6 hours at room temperature and then further
diluted to a concentration between 10 mg/mL and 100 mg/mL,
solutions of Sodium Chloride Injection, USP, and Lactated Ringer's
Injection, USP, may be stored frozen ���18��C
(0��F) for up to 30 days. Solutions prepared with Dextrose
Injection 5%, USP, may be stored frozen���18��C (0��F)
for up to 7 days. All thawed solutions should be used within
8 hours or discarded. Once thawed, solutions should not be refrozen. NOTE: TIMENTIN is
incompatible with Sodium Bicarbonate. Unused
solutions must be discarded after the time periods listed above.
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TIMENTIN is a sterile injectable antibacterial combination
consisting of the semisynthetic antibiotic ticarcillin disodium and
the��-lactamase inhibitor clavulanate potassium (the potassium
salt of clavulanic acid) for intravenous administration. Ticarcillin
is derived from the basic penicillin nucleus, 6-amino-penicillanic
acid. Chemically, ticarcillin disodium is N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-3-thiophenemalonamic
acid disodium salt and may be represented as: Clavulanic acid is produced by the fermentation
of Streptomyces clavuligerus. It is a��-lactam structurally related to the penicillins
and possesses the ability to inactivate a wide variety of��-lactamases
by blocking the active sites of these enzymes. Clavulanic acid is
particularly active against the clinically important plasmid-mediated�����lactamases frequently responsible for transferred drug
resistance to penicillins and cephalosporins. Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate
and may be represented structurally as: TIMENTIN is supplied as a white to pale yellow powder for reconstitution.
TIMENTIN is very soluble in water, its solubility being greater than
600 mg/mL. The reconstituted solution is clear, colorless or
pale yellow, having a pH of 5.5 to 7.5. For
the 3.1-gram dosage of TIMENTIN, the theoretical sodium content is
4.51 mEq (103.6 mg) per gram of TIMENTIN. The theoretical
potassium content is 0.15 mEq (6 mg) per gram of TIMENTIN.
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After an intravenous infusion (30 min.) of
3.1 grams of TIMENTIN, peak serum concentrations of both ticarcillin
and clavulanic acid are attained immediately after completion of infusion.
Ticarcillin serum levels are similar to those produced by the administration
of equivalent amounts of ticarcillin alone with a mean peak serum
level of 330 mcg/mL. The corresponding mean peak serum level
for clavulanic acid is 8 mcg/mL. (See following table.) SERUM LEVELS IN ADULTS AFTER A 30-MINUTE
IV INFUSION OF TIMENTIN TICARCILLIN
SERUM LEVELS (mcg/mL) CLAVULANIC ACID SERUM LEVELS (mcg/mL) The mean area under the serum concentration curve
was 485 mcg���hr/mL for ticarcillin and 8.2 mcg���hr/mL
for clavulanic acid. The mean serum half-lives
of ticarcillin and clavulanic acid in healthy volunteers are 1.1 hours
and 1.1 hours, respectively. In pediatric
patients receiving approximately 50 mg/kg of TIMENTIN (30:1 ratio
ticarcillin to clavulanate), mean ticarcillin serum half-lives were
4.4 hours in neonates (n = 18) and 1.0 hour in infants
and children (n = 41). The corresponding clavulanate serum
half-lives averaged 1.9 hours in neonates (n = 14)
and 0.9 hour in infants and children (n = 40). Area
under the serum concentration time curves averaged 339 mcg���hr/mL
in infants and children (n = 41), whereas the corresponding
mean clavulanate area under the serum concentration time curves was
approximately 7 mcg���hr/mL in the same population (n = 40). Approximately 60% to 70% of ticarcillin and approximately
35% to 45% of clavulanic acid are excreted unchanged in urine during
the first 6 hours after administration of a single dose of TIMENTIN
to normal volunteers with normal renal function. Two hours after an
intravenous injection of 3.1 grams of TIMENTIN, concentrations
of ticarcillin in urine generally exceed 1,500 mcg/mL. The corresponding
concentrations of clavulanic acid in urine generally exceed 40 mcg/mL.
By 4 to 6 hours after injection, the urine concentrations of
ticarcillin and clavulanic acid usually decline to approximately 190 mcg/mL
and 2 mcg/mL, respectively. Neither component of TIMENTIN is
highly protein bound; ticarcillin has been found to be approximately
45% bound to human serum protein and clavulanic acid approximately
25% bound. Somewhat higher and more prolonged
serum levels of ticarcillin can be achieved with the concurrent administration
of probenecid; however, probenecid does not enhance the serum levels
of clavulanic acid. Ticarcillin can be detected
in tissues and interstitial fluid following parenteral administration. Penetration of ticarcillin into bile and pleural fluid
has been demonstrated. The results of experiments involving the administration
of clavulanic acid to animals suggest that this compound, like ticarcillin,
is well distributed in body tissues. An inverse
relationship exists between the serum half-life of ticarcillin and
creatinine clearance. The dosage of TIMENTIN need only be adjusted
in cases of severe renal impairment. (See DOSAGE AND ADMINISTRATION.) Ticarcillin may be removed from patients undergoing dialysis;
the actual amount removed depends on the duration and type of dialysis.<br/>Microbiology: Ticarcillin is a semisynthetic antibiotic with a
broad spectrum of bactericidal activity against many gram-positive
and gram-negative aerobic and anaerobic bacteria. Ticarcillin is, however, susceptible to degradation by��-lactamases,
and therefore, the spectrum of activity does not normally include
organisms which produce these enzymes. Clavulanic
acid is a��-lactam, structurally related to the penicillins,
which possesses the ability to inactivate a wide range of��-lactamase
enzymes commonly found in microorganisms resistant to penicillins
and cephalosporins. In particular, it has good activity against the
clinically important plasmid-mediated��-lactamases frequently
responsible for transferred drug resistance. The formulation of ticarcillin with clavulanic acid in TIMENTIN
protects ticarcillin from degradation by��-lactamase enzymes
and effectively extends the antibiotic spectrum of ticarcillin to
include many bacteria normally resistant to ticarcillin and other��-lactam antibiotics. Thus, TIMENTIN possesses the distinctive
properties of a broad-spectrum antibiotic and a��-lactamase
inhibitor. Ticarcillin/clavulanic acid has been shown to be active
against most strains of the following microorganisms, both in vitro
and in clinical infections as described in the INDICATIONS AND USAGE
section.<br/>Gram-Positive Aerobes: Staphylococcus aureus (��-lactamase and non�����-lactamase���producing)��� Staphylococcus epidermidis (��-lactamase and non�����-lactamase���producing)��� ���Staphylococci that are resistant to methicillin/oxacillin
must be considered resistant to ticarcillin/clavulanic acid.<br/>Gram-Negative Aerobes: Citrobacter species (��-lactamase and non�����-lactamase���producing) Enterobacter species
including E. cloacae (��-lactamase
and non�����-lactamase���producing) (Although most
strains of Enterobacter species
are resistant in vitro, clinical efficacy has been demonstrated with
TIMENTIN in urinary tract infections and gynecologic infections caused
by these organisms.) Escherichia coli (��-lactamase and non�����-lactamase���producing) Haemophilus influenzae (��-lactamase and non�����-lactamase���producing) Klebsiella species including K. pneumoniae (��-lactamase and non�����-lactamase���producing) Pseudomonas species
including P. aeruginosa (��-lactamase
and non�����-lactamase���producing) Serratia marcescens (��-lactamase
and non�����-lactamase���producing) ��-lactamase���negative,
ampicillin-resistant (BLNAR) strains of H. influenzae must be considered resistant to ticarcillin/clavulanic
acid.<br/>Anaerobic Bacteria: Bacteroides fragilis group (��-lactamase and non�����-lactamase���producing) Prevotella (formerly Bacteroides) melaninogenicus (��-lactamase and non�����-lactamase���producing) The following in vitro data are available, but their clinical significance
is unknown. The following strains
exhibit an in vitro minimum inhibitory concentration (MIC) less than
or equal to the susceptible breakpoint for ticarcillin/clavulanic
acid. However, with the exception of organisms shown to respond to
ticarcillin alone, the safety and effectiveness of ticarcillin/clavulanic
acid in treating infections due to these microorganisms have not been
established in adequate and well-controlled clinical trials.<br/>Gram-Positive Aerobes: Staphylococcus saprophyticus (��-lactamase and non�����-lactamase���producing) Streptococcus agalactiae(Group B) Streptococcus bovis Streptococcus
pneumoniae(penicillin-susceptible strains
only) Streptococcus
pyogenes Viridans group streptococci<br/>Gram-Negative Aerobes: Acinetobacter baumannii (��-lactamase and non�����-lactamase���producing) Acinetobacter calcoaceticus (��-lactamase and non�����-lactamase���producing) Acinetobacter haemolyticus (��-lactamase and non�����-lactamase���producing) Acinetobacter lwoffi (��-lactamase and non�����-lactamase���producing) Moraxella catarrhalis (��-lactamase and non�����-lactamase���producing) Morganella morganii (��-lactamase and non�����-lactamase���producing) Neisseria gonorrhoeae (��-lactamase and non�����-lactamase���producing) Pasteurella multocida (��-lactamase and non�����-lactamase���producing) Proteus mirabilis (��-lactamase and non�����-lactamase���producing) Proteus penneri (��-lactamase and non�����-lactamase���producing) Proteus vulgaris (��-lactamase and non�����-lactamase���producing) Providencia rettgeri (��-lactamase and non�����-lactamase���producing) Providencia stuartii (��-lactamase and non�����-lactamase���producing) Stenotrophomonas maltophilia (��-lactamase and non�����-lactamase���producing)<br/>Anaerobic Bacteria: Clostridium species including C. perfringens, C. difficile, C. sporogenes, C. ramosum, and C. bifermentans (��-lactamase and non�����-lactamase���producing) Eubacterium species Fusobacterium species
including F. nucleatum and F. necrophorum (��-lactamase and
non�����-lactamase���producing) Peptostreptococcus species Veillonella species These are non�����-lactamase���producing
strains, and therefore, are susceptible to ticarcillin. In vitro synergism between TIMENTIN and gentamicin, tobramycin,
or amikacin against multiresistant strains of Pseudomonas aeruginosa has been demonstrated.<br/>Susceptibility Testing:<br/>Dilution Techniques: Quantitative methods are used to determine antimicrobial
MICs. These MICs provide estimates of the susceptibility of bacteria
to antimicrobial compounds. The MICs should be determined using a
standardized procedure. Standardized procedures are based on a dilution
method(broth or agar) or equivalent with standardized
inoculum concentrations and standardized concentrations of ticarcillin/clavulanate
potassium powder. The recommended dilution
pattern utilizes a constant level of 2 mcg/mL clavulanic acid
in all tubes with varying amounts of ticarcillin. MICs are expressed
in terms of the ticarcillin concentration in the presence of clavulanic
acid at a constant 2 mcg/mL. The MIC values should be interpreted
according to the following criteria: RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY
TESTING For Pseudomonas aeruginosa: For Enterobacteriaceae: For Staphylococci: A report of���Susceptible���indicates
that the pathogen is likely to be inhibited if the antimicrobial compound
in the blood reaches the concentrations usually achievable. 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
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 pathogen is not likely to be inhibited if the antimicrobial
compound in the blood reaches the concentrations usually achievable;
other therapy should be selected. Standardized
susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory
procedures. Standard ticarcillin/clavulanate potassium powder should
provide the following MIC values:<br/>Diffusion Techniques: Quantitative methods that require measurement of
zone diameters also provide reproducible estimates of the susceptibility
of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations.
This procedure uses paper disks impregnated with 85 mcg of ticarcillin/clavulanate
potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium)
to test the susceptibility of microorganisms to ticarcillin/clavulanic
acid. Reports from the laboratory providing
results of the standard single-disk susceptibility test with an 85 mcg
of ticarcillin/clavulanate potassium (75 mcg ticarcillin plus
10 mcg clavulanate potassium) disk should be interpreted according
to the following criteria: RECOMMENDED
RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING For Pseudomonas
aeruginosa: For Enterobacteriaceae: For Staphylococci: Interpretation should be as stated above for results
using dilution techniques. Interpretation involves correlation of
the diameter obtained in the disk test with the MIC for ticarcillin/clavulanic
acid. As with standardized dilution techniques,
diffusion methods require the use of laboratory control microorganisms
that are used to control the technical aspects of the laboratory procedures.
For the diffusion technique, the 85 mcg of ticarcillin/clavulanate
potassium (75 mcg ticarcillin plus 10 mcg clavulanate potassium)
disk should provide the following zone diameters in these laboratory
test quality control strains:<br/>Anaerobic Techniques: For anaerobic bacteria, the susceptibility to ticarcillin/clavulanic
acid can be determined by standardized test methods.
The MIC values obtained should be interpreted according to the following
criteria: RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC
ACID SUSCEPTIBILITY TESTING Interpretation is identical to that stated above
for results using dilution techniques. As with
other susceptibility techniques, the use of laboratory control microorganisms
is required to control the technical aspects of the laboratory standardized
procedures. Standardized ticarcillin/clavulanate potassium powder
should provide the following MIC values:
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TIMENTIN is contraindicated in patients with a history
of hypersensitivity reactions to any of the penicillins.
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Each 3.1-gram vial of TIMENTIN contains sterile
ticarcillin disodium equivalent to 3 grams ticarcillin and sterile
clavulanate potassium equivalent to 0.1 gram clavulanic acid. NDC 0029-6571-26 3.1-gram Vial TIMENTIN
is also supplied as: NDC 0029-6571-40 3.1-gram
ADD-VantageAntibiotic Vial Each 31 gram Pharmacy Bulk Package contains sterile ticarcillin
disodium equivalent to 30 grams ticarcillin and sterile clavulanate
potassium equivalent to 1 gram clavulanic acid. NDC 0029-6579-21 31 gram Pharmacy Bulk Package Vials of TIMENTIN should be stored at or below 24��C (75��F). NDC 0029-6571-31 TIMENTIN as an iso-osmotic, sterile,
nonpyrogenic, frozen solution in GALAXY(PL 2040)
Plastic Containers���supplied in 100 mL single-dose containers
equivalent to 3 grams ticarcillin and clavulanate potassium equivalent
to 0.1 gram clavulanic acid.
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General: While TIMENTIN possesses the characteristic low
toxicity of the penicillin group of antibiotics, periodic assessment
of organ system functions, including renal, hepatic, and hematopoietic
function, is advisable during prolonged therapy. Bleeding manifestations have occurred in some patients receiving��-lactam antibiotics. These reactions have been associated with
abnormalities of coagulation tests such as clotting time, platelet
aggregation, and prothrombin time and are more likely to occur in
patients with renal impairment. If bleeding manifestations appear,
treatment with TIMENTIN should be discontinued and appropriate therapy
instituted. TIMENTIN has only rarely been reported
to cause hypokalemia; however, the possibility of this occurring should
be kept in mind particularly when treating patients with fluid and
electrolyte imbalance. Periodic monitoring of serum potassium may
be advisable in patients receiving prolonged therapy. The theoretical sodium content is 4.51 mEq (103.6 mg)
per gram of TIMENTIN. This should be considered when treating patients
requiring restricted salt intake. As with any
penicillin, an allergic reaction, including anaphylaxis, may occur
during administration of TIMENTIN, particularly in a hypersensitive
individual. The possibility of superinfections
with mycotic or bacterial pathogens should be kept in mind, particularly
during prolonged treatment. If superinfections occur, appropriate
measures should be taken. Prescribing TIMENTIN
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.<br/>Information for Patients: Patients should be counseled that antibacterial
drugs, including TIMENTIN, should only be used to treat bacterial
infections. They do not treat viral infections (e.g., the common cold).
When TIMENTIN 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 TIMENTIN 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 2 or more months after having taken the last dose of the antibiotic.
If this occurs, patients should contact their physician as soon as
possible.<br/>Drug/Laboratory Test Interactions: As with other penicillins, the mixing of TIMENTIN
with an aminoglycoside in solutions for parenteral administration
can result in substantial inactivation of the aminoglycoside. Probenecid interferes with the renal tubular secretion
of ticarcillin, thereby increasing serum concentrations and prolonging
serum half-life of the antibiotic. In common
with other antibiotics, ticarcillin disodium/clavulanate potassium
may affect the gut flora, leading to lower estrogen reabsorption and
reduced efficacy of combined oral estrogen/progesterone contraceptives. High urine concentrations of ticarcillin may produce
false-positive protein reactions (pseudoproteinuria) with the following
methods: Sulfosalicylic acid and boiling test, acetic acid test, biuret
reaction, and nitric acid test. The bromphenol blue (MULTI-STIX) reagent strip test has been reported to be reliable. The presence of clavulanic acid in TIMENTIN may cause
a nonspecific binding of IgG and albumin by red cell membranes leading
to a false-positive Coombs test.<br/>Carcinogenesis, Mutagenesis, Impairment
of Fertility: Long-term studies in animals have not been performed
to evaluate carcinogenic potential. However, results from assays for
gene mutation in vitro using bacteria (Ames tests) and yeast, and
for chromosomal effects in vitro in human lymphocytes, and in vivo
in mouse bone marrow (micronucleus test) indicate that TIMENTIN is
without any mutagenic potential.<br/>Pregnancy (Category B): Reproduction studies have been performed in rats
given doses up to 1,050 mg/kg/day and have revealed no evidence
of impaired fertility or harm to the fetus due to TIMENTIN. There
are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only
if clearly needed.<br/>Nursing Mothers: It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk, caution
should be exercised when TIMENTIN is administered to a nursing woman.<br/>Pediatric Use: The safety and effectiveness of TIMENTIN have been
established in the age group of 3 months to 16 years. Use
of TIMENTIN in these age groups is supported by evidence from adequate
and well-controlled studies of TIMENTIN in adults with additional
efficacy, safety, and pharmacokinetic data from both comparative and
non-comparative studies in pediatric patients. There are insufficient
data to support the use of TIMENTIN in pediatric patients under 3 months
of age or for the treatment of septicemia and/or infections in the
pediatric population where the suspected or proven pathogen is H. influenzae type b. In those patients in whom meningeal seeding
from a distant infection site or in whom meningitis is suspected or
documented, or in patients who require prophylaxis against central
nervous system infection, an alternate agent with demonstrated clinical
efficacy in this setting should be used.
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As with other penicillins, neurotoxic reactions
may arise when very high doses of TIMENTIN are administered, especially
in patients with impaired renal function. (See WARNINGS and ADVERSE
REACTIONS���Central Nervous System.) In case of overdosage, discontinue TIMENTIN, treat symptomatically,
and institute supportive measures as required. Ticarcillin may be
removed from circulation by hemodialysis. The molecular weight, degree
of protein binding, and pharmacokinetic profile of clavulanic acid
together with information from a single patient with renal insufficiency
all suggest that this compound may also be removed by hemodialysis.
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ticarcillin disodium and clavulanate potassium
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TIMENTIN (Injection, Powder, For Solution)
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As with other penicillins, the following adverse
reactions may occur:<br/>Hypersensitivity Reactions: Skin rash, pruritus, urticaria, arthralgia, myalgia,
drug fever, chills, chest discomfort, erythema multiforme, toxic epidermal
necrolysis, Stevens-Johnson syndrome, and anaphylactic reactions.<br/>Central Nervous System: Headache, giddiness, neuromuscular hyperirritability,
or convulsive seizures.<br/>Gastrointestinal Disturbances: Disturbances of taste and smell, stomatitis, flatulence,
nausea, vomiting and diarrhea, epigastric pain, and pseudomembranous
colitis have been reported. Onset of pseudomembranous colitis symptoms
may occur during or after antibiotic treatment. (See WARNINGS.)<br/>Hemic and Lymphatic Systems: Thrombocytopenia, leukopenia, neutropenia, eosinophilia,
reduction of hemoglobin or hematocrit, and prolongation of prothrombin
time and bleeding time.<br/>Abnormalities of Hepatic and Renal
Function Tests: Elevation of serum aspartate aminotransferase (SGOT),
serum alanine aminotransferase (SGPT), serum alkaline phosphatase,
serum LDH, serum bilirubin. There have been reports of transient hepatitis
and cholestatic jaundice���as with some other penicillins and
some cephalosporins. Elevation of serum creatinine and/or BUN, hypernatremia,
reduction in serum potassium, and uric acid.<br/>Local Reactions: Pain, burning, swelling, and induration at the injection
site and thrombophlebitis with intravenous administration. Available safety data for pediatric patients treated
with TIMENTIN demonstrate a similar adverse event profile to that
observed in adult patients.
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SERIOUS AND OCCASIONALLY
FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED
IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY
TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY
AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE
BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY
WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS.
BEFORE INITIATING THERAPY WITH TIMENTIN, CAREFUL INQUIRY SHOULD BE
MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS,
CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS,
TIMENTIN SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT
WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT,
INCLUDING INTUBATION, SHOULD ALSO BE PROVIDED AS INDICATED. Clostridium difficile associated
diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including TIMENTIN, 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. When very high doses of TIMENTIN are administered,
especially in the presence of impaired renal function, patients may
experience convulsions. (See ADVERSE REACTIONS and OVERDOSAGE.)
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TIMENTIN is indicated in the treatment of infections
caused by susceptible strains of the designated microorganisms in
the conditions listed below: Septicemia (including bacteremia) caused
by��-lactamase���producing strains of Klebsiella spp., E. coli, S. aureus, or P. aeruginosa(or other Pseudomonas species) Lower Respiratory Infections caused by��-lactamase���producing strains of S. aureus, H. influenzae, or Klebsiella spp. Bone and Joint Infections caused by��-lactamase���producing strains of S. aureus Skin and Skin Structure Infections caused
by��-lactamase���producing strains of S. aureus, Klebsiella spp., or E. coli Urinary Tract Infections (complicated and
uncomplicated) caused by��-lactamase���producing strains
of E. coli, Klebsiella spp., P. aeruginosa(or other Pseudomonas spp.), Citrobacter spp., Enterobacter cloacae, S. marcescens, or S. aureus Gynecologic Infections endometritis
caused by��-lactamase���producing strains of P. melaninogenicus, Enterobacter spp. (including E. cloacae), E. coli, K. pneumoniae, S. aureus, or S. epidermidis Intra-abdominal
Infections peritonitis caused by��-lactamase���producing
strains of E. coli, K. pneumoniae, or B. fragilisgroup Efficacy for this organism in this organ system
was studied in fewer than 10 infections. NOTE: For information on use in pediatric
patients (���3 months of age) see PRECAUTIONS���Pediatric
Use and CLINICAL STUDIES sections. There are insufficient data to
support the use of TIMENTIN in pediatric patients under 3 months
of age or for the treatment of septicemia and/or infections in the
pediatric population where the suspected or proven pathogen is H. influenzaetype b. While TIMENTIN
is indicated only for the conditions listed above, infections caused
by ticarcillin-susceptible organisms are also amenable to treatment
with TIMENTIN due to its ticarcillin content. Therefore, mixed infections
caused by ticarcillin-susceptible organisms and��-lactamase���producing
organisms susceptible to ticarcillin/clavulanic acid should not require
the addition of another antibiotic. Appropriate
culture and susceptibility tests should be performed before treatment
in order to isolate and identify organisms causing infection and to
determine their susceptibility to ticarcillin/clavulanic acid. Because
of its broad spectrum of bactericidal activity against gram-positive
and gram-negative bacteria, TIMENTIN is particularly useful for the
treatment of mixed infections and for presumptive therapy prior to
the identification of the causative organisms. TIMENTIN has been shown
to be effective as single drug therapy in the treatment of some serious
infections where normally combination antibiotic therapy might be
employed. Therapy with TIMENTIN may be initiated before results of
such testsare known when there is reason to believe the infection
may involve any of the��-lactamase���producing organisms
listed above. Based on the in vitro synergism
between ticarcillin/clavulanic acid and aminoglycosides against certain
strains of P. aeruginosa, combined
therapy has been successful, especially in patients with impaired
host defenses. Both drugs should be used in full therapeutic doses. To reduce the development of drug-resistant bacteria
and maintain the effectiveness of TIMENTIN and other antibacterial
drugs, TIMENTIN 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.
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TIMENTIN
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