Ticarcillin-Clavulanate

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# Overview
Ticarcillin-Clavulanate is an antibiotic that is FDA approved for the treatment of septicemia,lower Respiratory Infections,bone and Joint Infections,skin and skin Structure infections, urinary tract infections,gynecologic Infections and intra-abdominal infections.   Common adverse reactions include phlebitis, rash, diarrhea,nausea, eosinophilia,
thrombocytopenia, leukopenia, neutropenia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- TIMENTIN is indicated in the treatment of infections caused by susceptible isolates of the designated bacteria in the conditions listed below:
Septicemia
- Septicemia (including bacteremia) caused by lactamaseproducing isolates of Klebsiella spp.*, Escherichia coli*, Staphylococcus aureus*, or Pseudomonas aeruginosa- (or other Pseudomonas species*)
Lower Respiratory Infections
- Lower respiratory infections caused by lactamaseproducing isolates of S. aureus, Haemophilus influenzae*, or Klebsiella spp.*
Bone and Joint Infections
- Bone and joint infections caused by lactamaseproducing isolates of S. aureus
Skin and Skin Structure Infections
- Skin and skin structure infections caused by lactamaseproducing isolates of S. aureus, Klebsiella spp.*, or E. coli*
Urinary Tract Infections
- Urinary tract infections (complicated and uncomplicated) caused by lactamaseproducing isolates of E. coli, Klebsiella spp., P. aeruginosa- (or other Pseudomonas spp.*), Citrobacter spp.*, Enterobacter cloacae*, Serratia marcescens*, or S. aureus*
Gynecologic Infections
- Endometritis caused by lactamaseproducing isolates of Prevotella melaninogenicus*, Enterobacter spp. (including E. cloacae*), E. coli, Klebsiella pneumoniae*, S. aureus, or Staphylococcus epidermidis
Intra-abdominal Infections
- Peritonitis caused by lactamaseproducing isolates of E. coli, K. pneumoniae, or Bacteroides fragilis- group
- Efficacy for this organism in this organ system was studied in fewer than 10 infections.
Usage
- To reduce the development of drugresistant bacteria and maintain the effectiveness of TIMENTIN and other antibacterial drugs, TIMENTIN should be used only to treat 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.

# Dosage
- The usual recommended dosage for systemic and urinary tract infections for adults is 3.1 grams of TIMENTIN (3 grams ticarcillin and 100 mg clavulanic acid) given every 4 to 6 hours.
- For gynecologic infections, TIMENTIN should be administered as follows (based on ticarcillin content): Moderate infections, 200 mg/kg/day in divided doses every 6 hours; 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 given in divided doses every 4 to 6 hours.
- The duration of therapy depends upon the severity of infection. The usual duration is 10 to 14 days; however, in difficult and complicated infections, more prolonged therapy may be required.

# Renal Impairment
For patients with 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 in Table 1.

# DOSAGE FORMS AND STRENGTHS
- The 3.1gram glass vial of TIMENTIN for Injection is a white to pale yellow sterile powder for reconstitution containing ticarcillin disodium equivalent to 3 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.
- The 31gram Pharmacy Bulk Package of TIMENTIN for Injection is a white to pale yellow sterile powder for reconstitution containing ticarcillin disodium equivalent to 30 grams ticarcillin and clavulanate potassium equivalent to 1 gram clavulanic acid.
- The 100-mL single-dose GALAXY Container (PL 2040 Plastic) of TIMENTIN is a frozen solution containing ticarcillin disodium equivalent to 3.0 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding FDA-Labeled Use of Ticarcillin-Clavulanate in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Ticarcillin-Clavulanate in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

# Indications
- TIMENTIN is indicated in the treatment of infections caused by susceptible isolates of the designated bacteria in the conditions listed below:
Septicemia
- Septicemia (including bacteremia) caused by lactamaseproducing isolates of Klebsiella spp.*, Escherichia coli*, Staphylococcus aureus*, or Pseudomonas aeruginosa- (or other Pseudomonas species*)
Lower Respiratory Infections
- Lower respiratory infections caused by lactamaseproducing isolates of S. aureus, Haemophilus influenzae*, or Klebsiella spp.*
Bone and Joint Infections
- Bone and joint infections caused by lactamaseproducing isolates of S. aureus
Skin and Skin Structure Infections
- Skin and skin structure infections caused by lactamaseproducing isolates of S. aureus, Klebsiella spp.*, or E. coli*
Urinary Tract Infections
- Urinary tract infections (complicated and uncomplicated) caused by lactamaseproducing isolates of E. coli, Klebsiella spp., P. aeruginosa- (or other Pseudomonas spp.*), Citrobacter spp.*, Enterobacter cloacae*, Serratia marcescens*, or S. aureus*
Gynecologic Infections
- Endometritis caused by lactamaseproducing isolates of Prevotella melaninogenicus*, Enterobacter spp. (including E. cloacae*), E. coli, Klebsiella pneumoniae*, S. aureus, or Staphylococcus epidermidis
Intra-abdominal Infections
- Peritonitis caused by lactamaseproducing isolates of E. coli, K. pneumoniae, or Bacteroides fragilis- group
- Efficacy for this organism in this organ system was studied in fewer than 10 infections.
Usage
- To reduce the development of drugresistant bacteria and maintain the effectiveness of TIMENTIN and other antibacterial drugs, TIMENTIN should be used only to treat 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.

# Dosage(3 Months of Age)
- Patients <60 kg: Mild to moderate infections, 200 mg/kg/day based on ticarcillin content in divided doses every 6 hours; severe infections, 300 mg/kg/day in divided doses every 4 hours.
- Patients 60 kg: Mild to moderate infections, 3.1 grams every 6 hours; severe infections, 3.1 grams every 4 hours.

# Renal Impairment
For patients with 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 in Table 1.

# DOSAGE FORMS AND STRENGTHS
- The 3.1gram glass vial of TIMENTIN for Injection is a white to pale yellow sterile powder for reconstitution containing ticarcillin disodium equivalent to 3 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.
- The 31gram Pharmacy Bulk Package of TIMENTIN for Injection is a white to pale yellow sterile powder for reconstitution containing ticarcillin disodium equivalent to 30 grams ticarcillin and clavulanate potassium equivalent to 1 gram clavulanic acid.
- The 100-mL single-dose GALAXY Container (PL 2040 Plastic) of TIMENTIN is a frozen solution containing ticarcillin disodium equivalent to 3.0 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Ticarcillin-Clavulanate in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Ticarcillin-Clavulanate in pediatric patients.

# Contraindications
- TIMENTIN is contraindicated in patients who have a history of hypersensitivity reaction (e.g., anaphylaxis or erythema multiforme) to TIMENTIN or to other lactam antibacterials (e.g., penicillins and cephalosporins).

# Warnings
Anaphylactic Reactions
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with TIMENTIN, inquire about previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue TIMENTIN and institute appropriate therapy.
Clostridium difficile Associated Diarrhea
- 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 antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Convulsions
- Patients may experience convulsions when the dose of TIMENTIN exceeds the recommended dose, especially in the presence of impaired renal function.
Risk of Bleeding
- Some patients receiving -lactam antibacterials have experienced bleeding associated with abnormalities in coagulation tests. These adverse reactions are more likely to occur in patients with renal impairment. If bleeding manifestations appear, treatment with TIMENTIN should be discontinued and appropriate therapy instituted.
Potential for Microbial Overgrowth or Bacterial Resistance
- The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, appropriate measures should be taken.
Development of Drug-Resistant Bacteria
- Prescribing TIMENTIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria.
Interference with Laboratory Tests
- High urine concentrations of ticarcillin may produce false-positive protein reactions (pseudoproteinuria).
- Clavulanic acid may cause a nonspecific binding of IgG and albumin by red cell membranes, leading to a false-positive Coombs test.
Electrolyte Imbalance
- Hypokalemia has been reported during treatment with TIMENTIN. Serum potassium should be monitored in patients with fluid and electrolyte imbalance and 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.

# Adverse Reactions

## Clinical Trials Experience
- The following are discussed in more detail in other sections of the labeling:
- Anaphylactic Reactions
- Clostridium difficile Associated Diarrhea.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions occurring in 1% of 867 patients receiving TIMENTIN 3.1 grams in clinical studies included rash, nausea, diarrhea, and phlebitis at the injection site. The most common laboratory abnormalities (3%) were elevations in eosinophils, serum aspartate aminotransferase (AST), and serum alanine aminotransferase (ALT).
- Available safety data for pediatric patients treated with TIMENTIN demonstrate a similar adverse event profile to that observed in adult patients.

## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of TIMENTIN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These adverse reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to TIMENTIN.
- Hypersensitivity Reactions: Skin rash, pruritus, urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, anaphylactic reactions, and bullous reactions (including erythema multiforme, toxic epidermal necrolysis, and StevensJohnson syndrome).
- 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 antibacterial treatment.
- 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 AST, ALT, serum alkaline phosphatase, serum LDH, and 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.

# Drug Interactions
Aminoglycosides
- The mixing of TIMENTIN with an aminoglycoside in solutions for parenteral administration can result in substantial inactivation of the aminoglycoside.
Probenecid
- Probenecid interferes with the renal tubular secretion of ticarcillin, thereby increasing serum concentrations and prolonging serum halflife of ticarcillin. Probenecid does not affect the serum levels of clavulanic acid.
Oral Contraceptives
- Ticarcillin disodium/clavulanate potassium may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.
Effects on Laboratory Tests
- High urine concentrations of ticarcillin may produce falsepositive protein reactions (pseudoproteinuria) with certain methods. The bromphenol blue reagent strip test has been reported to be a reliable method for testing protein reactions.
- Clavulanic acid in TIMENTIN may cause a nonspecific binding of IgG and albumin by red cell membranes, leading to a falsepositive Coombs test. A positive Coombs test should be interpreted with caution during treatment with TIMENTIN

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Category B.
- Reproduction studies have been performed in rats given doses up to 1,050 mg/kg/day (approximately half of the recommended human dose based on body surface area) and have revealed no evidence of harm to the fetus due to TIMENTIN. There are, however, no adequate and wellcontrolled 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.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ticarcillin-Clavulanate in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ticarcillin-Clavulanate during labor and delivery.

### Nursing Mothers
- It is not known whether ticarcillin or clavulanic acid 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 wellcontrolled studies of TIMENTIN in adults with additional efficacy, safety, and pharmacokinetic data from both comparative and noncomparative studies in pediatric patients. There are insufficient data to support the use of TIMENTIN in pediatric patients under 3 months of age.
- If meningitis is suspected or documented, an alternative agent with demonstrated clinical efficacy in this setting should be used.

### Geriatic Use
- An analysis of clinical studies of TIMENTIN was conducted to determine whether subjects aged 65 and older 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 older 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.
- 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.

### Gender
There is no FDA guidance on the use of Ticarcillin-Clavulanate with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ticarcillin-Clavulanate with respect to specific racial populations.

### Renal Impairment
Ticarcillin is predominantly excreted by the kidney. Dosage adjustments should be made for patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Ticarcillin-Clavulanate in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ticarcillin-Clavulanate in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ticarcillin-Clavulanate in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

# Administration and Directions for Use
- TIMENTIN should be administered by intravenous infusion over a 30-minute period.
Directions for Reconstitution and Further Dilution: 3.1gram Glass Vials: The 3.1gram 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. The color of reconstituted solutions of TIMENTIN normally ranges from light to dark yellow, depending on concentration, duration, and temperature of storage.
- The dissolved drug should be further diluted to desired volume using the recommended solution listed under Stability to a concentration between 10 mg/mL to 100 mg/mL.
- Pharmacy Bulk Package: The container closure may be penetrated only one time utilizing a suitable sterile transfer device or dispensing set that allows measured distribution of the contents. A sterile substance that must be reconstituted prior to use may require a separate closure entry.
- Restrict use of Pharmacy Bulk Packages to an aseptic area such as a laminar flow hood.
- Reconstituted contents of the vial should be withdrawn immediately. However, if this is not possible, aliquoting operations must be completed within 4 hours of reconstitution. Discard the reconstituted stock solution 4 hours after initial entry.
- Add 76 mL of Sterile Water for Injection, USP, or Sodium Chloride Injection, USP, to the 31gram Pharmacy Bulk Package and shake well. For ease of reconstitution, the diluent may be added in 2 portions. Each 1 mL of the resulting concentrated stock solution contains approximately 300 mg of ticarcillin and 10 mg of clavulanic acid.
- The desired dosage should be withdrawn from the stock solution and further diluted to desired volume using the recommended solution listed under Stability  to a concentration between 10 mg/mL to 100 mg/mL.
- Directions for Intravenous Infusion: After reconstitution and further dilution and prior to administration, TIMENTIN should be inspected visually for particulate matter. If particulate matter is present, the solution should be discarded.
- The solution of reconstituted drug may be administered over a 30-minute period by direct infusion or through a Ytype intravenous infusion set. If this method of administration is used, it is advisable to temporarily discontinue 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.
- GALAXY Container (PL 2040 Plastic): Prior to administration, TIMENTIN should be inspected visually for particulate matter. If particulate matter is present, the solution should be discarded.
Caution: Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.
Preparation for Administration: See How Supplied/Storage and Handling for thawing and handling instructions:
- Suspend the container from eyelet support.
- Remove protector from outlet port at bottom of container.
- Attach administration set. Refer to complete directions accompanying set.

### Monitoring
There is limited information regarding Monitoring of Ticarcillin-Clavulanate in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Ticarcillin-Clavulanate in the drug label.

# Overdosage
- In case of overdosage, discontinue TIMENTIN, treat symptomatically, and institute supportive measures as required. Ticarcillin and clavulanic acid may be removed from circulation by hemodialysis.

# Pharmacology

## Mechanism of Action
- Ticarcillin disrupts bacterial cell wall development by inhibiting peptidoglycan synthesis and/or by interacting with penicillinbinding proteins.
- Ticarcillin is susceptible to degradation by lactamases, so the spectrum of activity does not normally include organisms which produce these enzymes.
- Clavulanic acid is a lactam, structurally related to the penicillins, which inactivates some lactamase enzymes that are commonly found in bacteria resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmidmediated lactamases frequently responsible for transferred drug resistance.
- The formulation of ticarcillin with clavulanic acid in TIMENTIN protects ticarcillin from degradation by lactamase enzymes, effectively extending the antibacterial spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other lactam antibacterials.

## Structure
- TIMENTIN (ticarcillin disodium and clavulanate potassium) for Injection, 3.1gram glass vial, 31gram Pharmacy Bulk Package, and TIMENTIN (ticarcillin disodium and clavulanate potassium) Injection in the GALAXY Container (PL 2040 Plastic) are a combination of 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, 6aminopenicillanic acid.
- Chemically, ticarcillin disodium is N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclohept-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 plasmidmediated 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-azabicycloheptane-2-carboxylate and may be represented structurally as:
- TIMENTIN (ticarcillin disodium and clavulanate potassium) for Injection, the 3.1gram glass vial or the 31gram Pharmacy Bulk Package, are white to pale yellow sterile powders to be reconstituted and diluted for intravenous infusion. The reconstituted solution is clear, colorless or pale yellow, with a pH of 5.5 to 7.5. The 3.1gram glass vial of TIMENTIN for Injection contains ticarcillin disodium equivalent to 3 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid. The 31gram TIMENTIN for Injection Pharmacy Bulk Package contains ticarcillin disodium equivalent to 30 grams ticarcillin and clavulanate potassium equivalent to 1 gram clavulanic acid.
- TIMENTIN (ticarcillin disodium and clavulanate potassium) Injection in the GALAXY Container (PL 2040 Plastic) is an isoosmotic, sterile, nonpyrogenic, frozen solution containing 3.0 grams ticarcillin as ticarcillin disodium and 0.1 gram clavulanic acid as clavulanate potassium. Approximately 0.3 gram sodium citrate hydrous, USP, is added as a buffer. Sodium hydroxide is used to adjust pH and convert ticarcillin monosodium to ticarcillin disodium. The pH may have been adjusted with hydrochloric acid. The solution is intended for intravenous use after thawing to room temperature. The pH of thawed solution ranges from 5.5 to 7.5.
- The GALAXY container is fabricated from a specially designed multilayer plastic, PL 2040. Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.
- 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.
- For the 3.1-gram dosage of TIMENTIN in the GALAXY Container, the theoretical total sodium content of the 100-mL solution is 18.7 mEq (429 mg), of which 15.6 mEq (359 mg) is contributed by the ticarcillin disodium component of TIMENTIN. The total theoretical potassium content of the 100-mL solution is 0.50 mEq (19.63 mg).

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ticarcillin-Clavulanate in the drug label.

## Pharmacokinetics
Absorption
- After an intravenous infusion (30 minutes) of 3.1 grams of TIMENTIN, peak serum concentrations of both ticarcillin and clavulanic acid were attained immediately after completion of the infusion. Ticarcillin serum levels were similar to those produced by the administration of equivalent amounts of ticarcillin alone with a mean peak serum level of 324 mcg/mL. The corresponding mean peak serum level for clavulanic acid was 8 mcg/mL. (See Table 2.)
- The mean area under the serum concentration curve was 485 mcghr/mL for ticarcillin and 8.2 mcghr/mL for clavulanic acid.
Distribution
- Ticarcillin has been found to be approximately 45% bound to human serum protein and clavulanic acid approximately 25% bound. Ticarcillin can be detected in tissues and interstitial fluid following parenteral administration.
- Distribution 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.
Elimination
- 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.
- The mean serum halflife of both ticarcillin and clavulanic acid in healthy volunteers was 1.1 hours.
- Pediatrics: In pediatric patients receiving approximately 50 mg/kg of TIMENTIN (30:1 ratio ticarcillin to clavulanate), mean ticarcillin serum halflives were 4.4 hours in neonates (n = 18) and 1.0 hour in infants and children (n = 41). The corresponding clavulanate serum halflives 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 mcghr/mL in infants and children (n = 41), whereas the corresponding mean clavulanate area under the serum concentration time curves was approximately 7 mcghr/mL in the same population (n = 40).
Renal Impairment
- An inverse relationship exists between the serum halflife of ticarcillin and creatinine clearance. The halflife of ticarcillin in patients with renal failure is approximately 13 hours. The dosage of TIMENTIN need only be adjusted in cases of severe renal impairment.
- Ticarcillin may be removed from patients undergoing dialysis; the actual amount removed depends on the duration and type of dialysis.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Longterm studies in animals have not been performed to evaluate carcinogenic potential. Results from in vitro assays in bacteria (Ames tests), yeast, and human lymphocytes, and in vivo in mouse bone marrow (micronucleus test) indicate TIMENTIN is without genotoxic potential.
- Reproduction studies have been performed in rats given doses up to 1,050 mg/kg/day (approximately half of the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility due to TIMENTIN.

# Clinical Studies
- TIMENTIN has been studied in 296 pediatric patients (excluding neonates and infants less than 3 months) in 6 controlled clinical trials. The majority of patients studied had intraabdominal infections, and the primary comparator was clindamycin and gentamicin with or without ampicillin. At the endoftherapy 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 had a broad range of presenting diagnoses including: Infections in bone and joint, skin and skin structure, lower respiratory tract, urinary tract, as well as intraabdominal 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. Efficacy rates were comparable to those obtained in controlled trials.
- The adverse event profile in these 704 pediatric patients treated with TIMENTIN was comparable to that seen in adult patients.

# How Supplied
- Each 3.1gram vial of TIMENTIN for Injection contains sterile ticarcillin disodium equivalent to 3 grams ticarcillin and sterile clavulanate potassium equivalent to 0.1 gram clavulanic acid.
- Each 31gram Pharmacy Bulk Package of TIMENTIN for Injection contains sterile ticarcillin disodium equivalent to 30 grams ticarcillin and sterile clavulanate potassium equivalent to 1 gram clavulanic acid.
- Each 100mL single-dose GALAXY Container (PL 2040 Plastic) of TIMENTIN Injection contains ticarcillin disodium equivalent to 3.0 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.

## Storage
- 3.1-gram Vials and 31-gram Pharmacy Bulk Packages of TIMENTIN for Injection should be stored at or below 25C (77F).
- GALAXY Containers (PL 2040 Plastic) of TIMENTIN Injection should be stored at or below -20C (-4F). Avoid unnecessary handling of containers.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Drug Resistance: Inform patients 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, inform patients 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.
Clostridium difficile Associated Diarrhea: Inform patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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 their last dose of the antibacterial. If this occurs, advise patients to contact their physician as soon as possible.
Allergic Reactions: Inform patients that TIMENTIN contains a penicillin that can cause allergic reactions in some individuals.

# Precautions with Alcohol
- Alcohol-Ticarcillin-Clavulanate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- TIMENTIN

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price