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Timentin Add-Vantage

Generic Name: tiarcillin disodium and clavulanate potassium
Dosage Form: injection, powder, for solution

TIMENTIN®
(sterile ticarcillin disodium and clavulanate potassium)
for Intravenous Administration
ADD-VANTAGE® ANTIBIOTIC VIAL

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TIMENTIN (ticarcillin disodium and clavulanate potassium) and other antibacterial drugs, TIMENTIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Timentin Add-Vantage Description

TIMENTIN is a sterile injectable antibacterial combination consisting of the semisynthetic antibiotic ticarcillin disodium, and the β-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 Streptomycesclavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins.

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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.

Timentin Add-Vantage - Clinical Pharmacology

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 was 8 mcg/mL. (See following table.)

SERUM LEVELS IN ADULTS

AFTER A 30-MINUTE IV INFUSION OF TIMENTIN®

TICARCILLIN SERUM LEVELS (mcg/mL)

Dose

0

15 min.

30 min.

1 hr.

1.5 hr.

3.5 hr.

5.5 hr.

3.1 gram

324

223

176

131

90

27

6

(293 to 388)

(184 to 293)

(135 to 235)

(102 to 195)

(65 to 119)

(19 to 37)

(5 to 7)

CLAVULANIC ACID SERUM LEVELS (mcg/mL)

Dose

0

15 min.

30 min.

1 hr.

1.5 hr.

3.5 hr.

5.5 hr.

3.1 gram

8.0

4.6

2.6

1.8

1.2

0.3

0

(5.3 to 10.3)

(3.0 to 7.6)

(1.8 to 3.4)

(1.6 to 2.2)

(0.8 to 1.6)

(0.2 to 0.3)

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.

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 β-lactamases, and therefore, the spectrum of activity does not normally include organisms which produce these enzymes.

Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance.

The formulation of ticarcillin with clavulanic acid in TIMENTIN protects ticarcillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other β-lactam antibiotics. Thus, TIMENTIN possesses the distinctive properties of a broad-spectrum antibiotic and a β-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.

Gram-Positive Aerobes

Staphylococcus aureus (β-lactamase and non−β-lactamase−producing)*

Staphylococcus epidermidis (β-lactamase and non−β-lactamase−producing)*

*Staphylococci that are resistant to methicillin/oxacillin must be considered resistant to ticarcillin/clavulanic acid. 

Gram-Negative Aerobes

Citrobacter species (β-lactamase and non−β-lactamase−producing)

Enterobacterspecies including E. cloacae (β-lactamase and non−β-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 (β-lactamase and non−β-lactamase−producing)

Haemophilusinfluenzae (β-lactamase and non−β-lactamase−producing)

Klebsiella species including K. pneumoniae (β-lactamase and non−β-lactamase−producing)

Pseudomonas species including P. aeruginosa (β-lactamase and non−β-lactamase−producing)

Serratiamarcescens (β-lactamase and non−β-lactamase−producing) 

β-lactamase−negative, ampicillin-resistant (BLNAR) strains of H. influenzae must be considered resistant to ticarcillin/clavulanic acid.

Anaerobic Bacteria

Bacteroidesfragilis group (β-lactamase and non−β-lactamase−producing)

Prevotella(formerly Bacteroides)melaninogenicus (β-lactamase and non−β-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.

Gram-Positive Aerobes

Staphylococcus saprophyticus (β-lactamase and non−β-lactamase− producing)

Streptococcus agalactiae (Group B)

Streptococcus bovis

Streptococcus pneumoniae (penicillin-susceptible strains only) 

Streptococcus pyogenes

Viridans group streptococci

Gram-Negative Aerobes

Acinetobacterbaumannii (β-lactamase and non−β-lactamase−producing)

Acinetobactercalcoaceticus (β-lactamase and non−β-lactamase−producing)

Acinetobacterhaemolyticus (β-lactamase and non−β-lactamase−producing)

Acinetobacterlwoffi (β-lactamase and non−β-lactamase−producing)

Moraxellacatarrhalis (β-lactamase and non−β-lactamase−producing)

Morganellamorganii (β-lactamase and non−β-lactamase−producing)

Neisseriagonorrhoeae (β-lactamase and non−β-lactamase−producing)

Pasteurellamultocida (β-lactamase and non−β-lactamase−producing)

Proteus mirabilis (β-lactamase and non−β-lactamase−producing)

Proteus penneri (β-lactamase and non−β-lactamase−producing)

Proteus vulgaris (β-lactamase and non−β-lactamase−producing)

Providenciarettgeri (β-lactamase and non−β-lactamase−producing)

Providenciastuartii (β-lactamase and non−β-lactamase−producing)

Stenotrophomonasmaltophilia (β-lactamase and non−β-lactamase−producing)

Anaerobic Bacteria

Clostridium species including C. perfringens, C. difficile, C. sporogenes, C. ramosum, and C. bifermentans (β-lactamase and non−β-lactamase−producing)

Eubacterium species

Fusobacteriumspecies including F. nucleatum and F. necrophorum (β-lactamase and non−β-lactamase−producing)

Peptostreptococcusspecies

Veillonella species

These are non−β-lactamase−producing strains, and therefore, are susceptible to ticarcillin.

In vitro synergism between TIMENTIN and gentamicin, tobramycin, or amikacin against multiresistant strains of Pseudomonas aeruginosahas been demonstrated.

Susceptibility Testing

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 method1,3 (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:

MIC (mcg/mL)

Interpretation

≤64

Susceptible (S)

≥128

Resistant (R)

For Enterobacteriaceae:

MIC (mcg/mL)

Interpretation

≤16

Susceptible (S)

32-64

Intermediate (I)

≥128

Resistant (R)

For Staphylococci:

MIC (mcg/mL)

Interpretation

≤8

Susceptible (S)

≥16

Resistant (R)

* Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

Staphylococci that are susceptible to ticarcillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

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 values3:

Microorganism

MIC (mcg/mL)

Escherichia coli

ATCC 25922

4-16

Escherichia coli

ATCC 35218

8-32

Pseudomonas aeruginosa

ATCC 27853

8-32

Staphylococcus aureus

ATCC 29213

0.5-2

Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

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 procedure2,3 requires 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:

Zone Diameter (mm)

Interpretation

≥15

Susceptible (S)

≤14

Resistant (R)

For Enterobacteriaceae:

Zone Diameter (mm)

Interpretation

≥20

Susceptible (S)

15-19

Intermediate (I)

≤14

Resistant (R)

For Staphylococci§:

Zone Diameter (mm)

Interpretation

≥23

Susceptible (S)

≤22

Resistant (R)

§Staphylococci that are resistant to methicillin/oxacillin must be considered as resistant to ticarcillin/clavulanic acid.

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:

Microorganism

Zone Diameter (mm)

Escherichia coli

ATCC 25922

24-30

Escherichia coli

ATCC 35218

21-25

Pseudomonas aeruginosa

ATCC 27853

20-28

Staphylococcus aureus

ATCC 25923

29-37

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to ticarcillin/clavulanic acid can be determined by standardized test methods.3,4 The MIC values obtained should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR TICARCILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING||

MIC (mcg/mL)

Interpretation

≤32

Susceptible (S)

64

Intermediate (I)

≥128

Resistant (R)

||Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

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:

Agar dilution

Broth microdilution

MIC Range

MIC Range

Microorganism

(mcg/mL) ||

(mcg/mL)

Bacteroidesthetaiotaomicron

ATCC 29741

0.5-2

0.5-2

Eubacteriumlentum

ATCC 43055

16-64

8-32

Expressed as concentration of ticarcillin in the presence of clavulanic acid at a constant 2 mcg/mL.

Indications and Usage for Timentin Add-Vantage

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 β-lactamase−producing strains of Klebsiella spp.*, E. coli *, S. aureus*, or P. aeruginosa* (or other Pseudomonas species*)

Lower Respiratory Infections caused by β-lactamase−producing strains of S. aureus, H. influenzae*, or Klebsiellaspp.*

Bone and Joint Infections caused by β-lactamase−producing strains of S. aureus

Skin and Skin Structure Infections caused by β-lactamase−producing strains of S. aureus, Klebsiella spp.*, or E. coli*

Urinary Tract Infections (complicated and uncomplicated) caused by β-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 β-lactamase−producing strains of P. melaninogenicus*, Enterobacterspp. (including E. cloacae*), E. coli, K. pneumoniae*, S. aureus, or S. epidermidis

Intra-abdominal Infections peritonitis caused by β-lactamase−producing strains of E. coli, K. pneumoniae, or B. fragilis* group

*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. influenzae type 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 β-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 tests are known when there is reason to believe the infection may involve any of the β-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.

Contraindications

TIMENTIN is contraindicated in patients with a history of hypersensitivity reactions to any of the penicillins.

Warnings

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 difficileassociated 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. difficileproduces 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.)

Precautions

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 β-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.

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.

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.

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.

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.

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.

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.

Geriatric Use

An analysis of clinical studies of TIMENTIN was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1,078 subjects treated with at least one dose of TIMENTIN, 67.5% were <65 years old, and 32.5% were ≥65 years old. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE and ADMINISTRATION).

TIMENTIN contains 103.6 mg (4.51 mEq) of sodium per gram of TIMENTIN. At the usual recommended doses, patients would receive between 1,285 and 1,927 mg/day (56 and 84 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

Adverse Reactions

As with other penicillins, the following adverse reactions may occur:

Hypersensitivity Reactions

Skin rash, pruritus, urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylactic reactions.

Central Nervous System

Headache, giddiness, neuromuscular hyperirritability, or convulsive seizures.

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.)

Hemic and Lymphatic Systems

Thrombocytopenia, leukopenia, neutropenia, eosinophilia, reduction of hemoglobin or hematocrit, and prolongation of prothrombin time and bleeding time.

Abnormalities of Hepatic 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.

Renal and Urinary Effects

Hemorrhagic cystitis, elevation of serum creatinine and/or BUN, hypernatremia, reduction in serum potassium and uric acid.

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.

Drug Abuse and Dependence

Neither abuse of nor dependence on TIMENTIN has been reported.

Overdosage

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.

Timentin Add-Vantage Dosage and Administration

TIMENTIN should be administered by intravenous infusion (30 min.).

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.

Pediatric Patients (≥3 months)

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.

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.

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:

Creatinine clearance mL/min.

Dosage

over 60

3.1 grams every 4 hrs.

 

30 to 60

2 grams every 4 hrs.

 

10 to 30

2 grams every 8 hrs.

 

less than 10

2 grams every 12 hrs.

 

less than 10 with hepatic dysfunction

2 grams every 24 hrs.

 

patients on peritoneal dialysis

3.1 grams every 12 hrs.

patients on hemodialysis

2 grams every 12 hrs.

 

supplemented with 3.1

 

grams after each dialysis

 

NOTE: TIMENTIN in the ADD-VANTAGE® system should only be administered for 3.1-gram dosing.

The half-life of ticarcillin in patients with renal failure is approximately 13 hours.

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.

INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed.

This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container:

(Use Aseptic Technique)

1.
Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:

a. To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (see Figure 1), then pull straight up to remove the cap (see Figure 2).

NOTE: Do not access vial with syringe.

Figure 1

Figure 2

b. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the 3 tie strings, then pull back to remove the cover (see Figure 3).

Figure 3

2. Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately ½ turn (180°) after the first audible click (see Figure 4). The clicking sound does not assure a seal; the vial must be turned as far as it will go.

NOTE:Once vial is sealed, do not attempt to remove (see Figure 4).

Figure 4

3. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.

4. Label appropriately.

To Reconstitute the Drug:

1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.

2. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container (see Figure 5).

Figure 5

3. Pull the inner cap from the drug vial (see Figure 6). Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.

Figure 6

4. Mix container contents thoroughly and use within the specified time.

Preparation for Administration

(Use Aseptic Technique):

1.
Confirm the activation and admixture of vial contents.
2.
Check for leaks by squeezing container firmly. If leaks are found discard unit as sterility may be impaired.
3.
Close flow control clamp of administration set.
4.
Remove cover from outlet port at bottom of container.
5.
Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
6.
Lift the free end of the hanger loop on the bottom of the vial, breaking the 2 tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
7.
Squeeze and release drip chamber to establish proper fluid level in chamber.
8.
Open flow control clamp and clear air from set. Close clamp.
9.
Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
10.
Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

RECONSTITUTION DIRECTIONS

Intravenous Infusion

Use a 50-mL or 100-mL ADD-VANTAGE® DILUENT CONTAINER containing either Sodium Chloride Injection, USP, or 5% Dextrose in Water (refer to INSTRUCTIONS FOR USE section). The resulting concentration of the 3.1-gram dose reconstituted in 50 mL of diluent is approximately 60 mg/mL of ticarcillin and approximately 2 mg/mL of clavulanic acid. The resulting concentration of the 3.1-gram dose reconstituted in 100 mL of diluent is approximately 30 mg/mL of ticarcillin and approximately 1 mg/mL of clavulanic acid.

The solution of reconstituted drug may then be administered over a period of 30 minutes by direct infusion or through a Y-type intravenous infusion set, which may already be in place. If this method of administration is used, it is advisable to discontinue temporarily the administration of any other solutions during the infusion of TIMENTIN. 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.

STABILITY PERIOD

INTRAVENOUS SOLUTION

ROOM TEMPERATURE

(ticarcillin concentration of ~ 30 mg/mL or ~ 60 mg/mL)

21° to 24°C (70° to 75°F)

Sodium Chloride Injection, USP

24 hours

5% Dextrose in Water

12 hours

NOTE: TIMENTIN is incompatible with Sodium Bicarbonate.

Unused portions of solutions should be discarded after the time periods listed above.

Avoid excessive heat.

Protect from freezing.

How is Timentin Add-Vantage Supplied

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 0029-6571-40          3.1-gram ADD-VANTAGE® Antibiotic Vial

TIMENTIN is also supplied as:

NDC 0029-6571-26          3.1-gram 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

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.

Clinical Studies

TIMENTIN has been studied in a total of 296 pediatric patients (excluding neonates and infants less than 3 months) in 6 controlled clinical trials. The majority of patients studied had intra-abdominal infections, and the primary comparator was clindamycin and gentamicin with or without ampicillin. At the end-of-therapy visit, comparable efficacy was reported in the trial arms using TIMENTIN and an appropriate comparator.

TIMENTIN was also evaluated in an additional 408 pediatric patients (excluding neonates and infants less than 3 months) in 3 uncontrolled US clinical trials. Patients were treated across a broad range of presenting diagnoses including: Infections in bone and joint, skin and skin structure, lower respiratory tract, urinary tract, as well as intra-abdominal and gynecologic infections. Patients received TIMENTIN either 300 mg/kg/day (based on the ticarcillin component) divided every 4 hours for severe infection or 200 mg/kg/day (based on the ticarcillin component) divided every 6 hours for mild to moderate infections. The efficacy rates were comparable to those obtained in the controlled trials.

The adverse event profile in these 704 pediatric patients treated with TIMENTIN was comparable to that seen in adult patients.

REFERENCES

1.
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Seventh Edition. Approved Standard CLSI Document M7-A7, Vol. 26, No. 2. CLSI, Wayne, PA, Jan. 2006.
2.
Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests – Ninth Edition. Approved Standard CLSI Document M2-A9, Vol. 26, No. 1. CLSI, Wayne, PA, Jan. 2006.
3.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Eighteenth Informational Supplement. Approved Standard CLSI Document M100-S18, Vol. 28, No. 1. CLSI, Wayne, PA, Jan. 2008.
4.
Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – Seventh Edition. Approved Standard CSLI Document M11-A7, Vol. 27, No. 2. CLSI, Wayne, PA, 2007.

TIMENTIN is a registered trademark of GlaxoSmithKline.

The following are registered trademarks of their respective owners: ADD-VANTAGE/Hospira, Inc.; GALAXY/Baxter International Inc.; MULTI-STIX/Bayer Corporation.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2011, GlaxoSmithKline. All rights reserved.

June 2011

TMV:20PI

Principal Display Panel

NDC 0029-6571-40

TIMENTIN®

STERILE TICARCILLIN DISODIUM AND CLAVULANATE POTASSIUM

3.1 grams

Equivalent to TICARCILLIN, 3 GRAMS, CLAVULANIC ACID, 100 MG INJECTION

Rx only

Intravenous Infusion

Store dry powder at room temperature (70o – 75oF) or below.

Vial contains sterile ticarcillin disodium equivalent to 3 grams ticarcillin, and sterile clavulanate potassium equivalent to 100 mg clavulanic acid.

Dosage: See accompanying folder for complete prescribing information and instructions for using vial.

GlaxoSmithKline

Research Triangle Park, NC 27709

Made in England. Rev. 6/10

ADD-VANTAGE®*

ANTIBIOTIC VIAL TO BE USED WITH

ADD-VANTAGE®

DILUENT CONTAINER

LOT

EXP.

*ADD-Vantage® is a trademark of Hospira, Inc.

10000000082631

TIMENTIN  ADD-VANTAGE
ticarcillin disodium and clavulanate potassium injection, powder, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0029-6571
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TICARCILLIN DISODIUM (TICARCILLIN) TICARCILLIN 30 mg  in 1 mL
CLAVULANATE POTASSIUM (CLAVULANIC ACID) CLAVULANIC ACID 1 mg  in 1 mL
Product Characteristics
Color YELLOW (clear, colorless or pale yellow) Score     
Shape Size
Flavor Imprint Code
Contains         
Packaging
# Item Code Package Description
1 NDC:0029-6571-40 10 VIAL in 1 TRAY
1 100 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA062691 10/22/1990 11/30/2012
Labeler - GlaxoSmithKline LLC (167380711)
Revised: 09/2011
 
GlaxoSmithKline LLC
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