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Timentin (Lyophilisate) Instructions for Use

Marketing Authorization Holder

GlaxoSmithKline Trading, JSC (Russia)

Manufactured By

SmithKline Beecham Pharmaceuticals (UK)

ATC Code

J01CR03 (Ticarcillin and beta-lactamase inhibitor)

Active Substances

Clavulanic acid (Rec.INN registered by WHO)

Ticarcillin (Rec.INN registered by WHO)

Dosage Forms

Bottle Rx Icon Timentin Lyophilisate for preparation of solution for infusion 1.5 g+100 mg: vials 10 pcs.
Lyophilisate for preparation of solution for infusion 3 g+200 mg: vials 10 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion as a powder from white to light yellow in color.

1 vial
Ticarcillin (as sodium salt) 1.5 g
Clavulanic acid (as potassium salt) 100 mg

Glass vials (10) – cardboard packs.

Lyophilisate for preparation of solution for infusion as a powder from white to light yellow in color.

1 vial
Ticarcillin (as sodium salt) 3 g
Clavulanic acid (as potassium salt) 200 mg

Glass vials (10) – cardboard packs.

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic, resistant to penicillinase; active, including against Pseudomonas aeruginosa

Pharmacotherapeutic Group

Antibiotic, semi-synthetic penicillin + beta-lactamase inhibitor

Pharmacological Action

Timentin is a broad-spectrum penicillin antibiotic resistant to penicillinase. Timentin is a combination drug containing ticarcillin sodium – a semi-synthetic carboxypenicillin with a broad spectrum of bactericidal activity, and potassium clavulanate – a beta-lactamase inhibitor produced by many gram-negative and gram-positive bacteria.

The action of beta-lactamases can lead to the destruction of some antibacterial drugs before they begin to act on pathogens. Potassium clavulanate destroys this protective mechanism by blocking the action of enzymes, making bacteria sensitive to ticarcillin. Potassium clavulanate does not have antibacterial activity, but its combination with ticarcillin in Timentin results in a broad-spectrum antibiotic that is insensitive to beta-lactamases.

Timentin has a bactericidal effect in vitro against gram-negative bacteria: Acinetobacter spp., Moraxella catarrhalis, Citrobacter spp. (including Citrobacter freundii, Citrobacter diversus, Citrobacter amalonaticas), Enterobacter spp. (although many strains of Enterobacter spp. are resistant in vitro, clinical efficacy of ticarcillin with clavulanic acid has been demonstrated in urinary tract infections), Escherichia coli, Haemophilus influenzae, Klebsiella spp. (including Klebsiella pneumoniae), Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas spp. (including Pseudomonas aeruginosa, Pseudomonas maltophila), Salmonella spp., Serratia spp. (including Serratia marcescens); gram-positive bacteria: Staphylococcus aureus, Staphylococcus epidermidis (coagulase-negative strains), Staphylococcus saprophyticus, Streptococcus agalactiae* (group B), Streptococcus bovis*, Enterococcus faecalis*, Streptococcus pneumoniae*, Streptococcus pyogenes* (group A, beta-hemolytic), Streptococcus viridans; anaerobic bacteria Bacteroides spp., including the Bacteroides fragilis group (Bacteroides fragilis, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Bacteroides ovatus, Bacteroides distasonis), and non-Bacteroides fragilis (beta-melanogenic), Clostridium spp. (including Clostridium perfiingens, Clostridium difficile, Clostridium sporogenes, Clostridium ramosum, Clostridium bifermentans*), Eubacterium spp., Fusobacterium spp. (including Fusobacterium nucleatum and Fusobacterium necrophorum*), Peptococcus spp.*, Peptostreptococcus spp.*, Veillonella spp.*.

* strains sensitive to ticarcillin, not producing beta-lactamase.

Pharmacokinetics

The AUC for ticarcillin is 485 mcg/ml/h after administration of 3.1 g and 3.2 g. The corresponding values for clavulanic acid are 8.2 mcg/ml/h and 15.6 mcg/ml/h. After IV infusions of ticarcillin at doses of 3.1 g and 3.2 g over 30 min, Cmax in plasma is reached immediately after the end of the infusions and is 330 mcg/ml for both doses. The pharmacokinetic parameters for clavulanic acid are 8 mcg/ml (for 3.1 g ticarcillin) and 16 mcg/ml (for 3.2 g ticarcillin).

Serum concentrations in adults after a 30-minute infusion of ticarcillin at a dose of 3.2 g

Time Ticarcillin (mcg/ml) Clavulanic acid (mcg/ml)
0 336 301-386 15.8 11.7-21
15 min 214 180-258 8.3 6.4-10
30 min 186 160-218 5.2 3.5-6.3
1 h 122 108-136 3.4 1.9-4
1.5 h 78 33-113 2.5 1.3-3.4
3.5 h 29 19-44 0.5 0.2-0.8
5.5 h 10 5-15 0

Distribution

Ticarcillin is distributed in organs and tissues upon parenteral administration. Penetration of ticarcillin into bile, pleural fluid, and cerebrospinal fluid has been shown. T1/2 from plasma is inversely proportional to creatinine clearance. Plasma protein binding is 50% for ticarcillin and 25% for clavulanic acid.

Elimination

The mean T1/2 from serum, determined in healthy volunteers, for ticarcillin and clavulanic acid is 68 min and 64 min, respectively. Approximately 60-70% of ticarcillin and 35-45% of clavulanic acid is excreted unchanged by the kidneys within the first hours after administration of a single dose of the drug (in healthy volunteers with normal renal function). Two hours after IV infusion of 3.2 g of the drug, the concentration of ticarcillin in urine exceeds 1500 mcg/ml, and the concentration of clavulanic acid exceeds 70 mcg/ml. Four to six hours after administration of the drug at a dose of 3.2 g, the concentration in urine is 2 mcg/ml.

Pharmacokinetics in special clinical cases

Ticarcillin can be removed by dialysis, with the removal rate depending on the type of dialysis.

Indications

Timentin is indicated for the treatment of infections caused by pathogens with established or suspected sensitivity, such as

  • Bone and connective tissue infections caused by beta-lactamase-producing strains of Staphylococcus aureus;
  • Gynecological infections, including endometritis, caused by beta-lactamase-producing strains of Bacteroides melaninogenicus*, Enterobacter spp., including Enterobacter cloacae*, Escherichia coli, Klebsiella pneumoniae*, Staphylococcus aureus, Staphylococcus epidermidis;
  • Intra-abdominal infections, including peritonitis, caused by beta-lactamase-producing strains of Escherichia coli, Klebsiella pneumoniae and Bacteroides fragilis*;
  • Lower respiratory tract infections caused by beta-lactamase-producing strains of Staphylococcus aureus, Haemophilus influenzae* and Klebsiella spp.*;
  • Septicemia, including bacteremia, caused by beta-lactamase-producing strains of Klebsiella spp.*, Escherichia coli*, Staphylococcus aureus*, Pseudomonas aeruginosa* and other Pseudomonas spp.*;
  • Skin and subcutaneous tissue infections caused by beta-lactamase-producing strains of Staphylococcus aureus, Klebsiella spp.* and Escherichia coli*;
  • Urinary tract infections (uncomplicated and complicated) caused by beta-lactamase-producing strains of Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa* and other Pseudomonas spp.*, Citrobacter spp.*, Enterobacter cloacae*, Serratia marcescens* and Staphylococcus aureus*.

* efficacy against microorganisms has been demonstrated in fewer than 10 infections in each nosological group.

ICD codes

ICD-10 code Indication
A40 Streptococcal sepsis
A41 Other sepsis
J15 Bacterial pneumonia, not elsewhere classified
J20 Acute bronchitis
J42 Unspecified chronic bronchitis
K65.0 Acute peritonitis (including abscess)
K81.0 Acute cholecystitis
K81.1 Chronic cholecystitis
K83.0 Cholangitis
L01 Impetigo
L02 Cutaneous abscess, furuncle and carbuncle
L03 Cellulitis
L08.0 Pyoderma
M00 Pyogenic arthritis
M86 Osteomyelitis
N10 Acute tubulointerstitial nephritis (acute pyelonephritis)
N11 Chronic tubulointerstitial nephritis (chronic pyelonephritis)
N15.1 Renal and perinephric abscess
N30 Cystitis
N34 Urethritis and urethral syndrome
N41 Inflammatory diseases of prostate
N70 Salpingitis and oophoritis
N71 Inflammatory disease of uterus, excluding cervix (including endometritis, myometritis, metritis, pyometra, uterine abscess)
N72 Inflammatory disease of cervix uteri (including cervicitis, endocervicitis, exocervicitis)
N73.0 Acute parametritis and pelvic cellulitis
T79.3 Posttraumatic wound infection, not elsewhere classified
Z29.2 Other prophylactic chemotherapy (administration of antibiotics for prophylactic purposes)
ICD-11 code Indication
1B70.1 Streptococcal cellulitis of the skin
1B70.2 Staphylococcal cellulitis of the skin
1B70.Z Bacterial cellulitis or lymphangitis caused by unspecified bacterium
1B72.0 Bullous impetigo
1B72.1 Nonbullous impetigo
1B72.Z Impetigo, unspecified
1B75.0 Furuncle
1B75.1 Carbuncle
1B75.2 Furunculosis
1B75.3 Pyogenic skin abscess
1G40 Sepsis without septic shock
CA20.1Z Chronic bronchitis, unspecified
CA40.0Z Bacterial pneumonia, unspecified
CA42.Z Acute bronchitis, unspecified
DC12.0Z Acute cholecystitis, unspecified
DC12.1 Chronic cholecystitis
DC13 Cholangitis
DC50.0 Primary peritonitis
DC50.2 Peritoneal abscess
DC50.Z Peritonitis, unspecified
EB21 Pyoderma gangrenosum
FA1Z Infectious arthropathies, unspecified
FB84.Z Osteomyelitis or osteitis, unspecified
GA01.Z Inflammatory diseases of uterus, except cervix, unspecified
GA05.0 Acute inflammatory disease of female pelvic organs
GA07.Z Salpingitis and oophoritis, unspecified
GA91.Z Inflammatory and other diseases of prostate, unspecified
GB50 Acute tubulo-interstitial nephritis
GB51 Acute pyelonephritis
GB55.Z Chronic tubulo-interstitial nephritis, unspecified
GB59 Abscess of kidney or perirenal tissue
GB5Z Renal tubulo-interstitial diseases, unspecified
GC00.Z Cystitis, unspecified
GC02.Z Urethritis and urethral syndrome, unspecified
NF0A.3 Posttraumatic wound infection, not elsewhere classified
QC05.Y Other specified prophylactic measures
GA0Z Inflammatory diseases of female genital tract, unspecified
XA5WW1 Cervix uteri

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Timentin can be administered as an IV drip infusion or IV bolus injection. The drug is not intended for IM injection. The intervals between infusions should be at least 4 hours. Treatment should be continued for 48-72 hours after the disappearance of clinical symptoms.

For adults and children weighing more than 40 kg the average dose of Timentin is 3 g every 6 hours or 5 g every 8 hours. The maximum dose is 3 g every 4 hours.

For children weighing less than 40 kg the average dose of Timentin is 75 mg/kg every 8 hours. The maximum dose is 75 mg/kg every 6 hours.

For premature infants weighing less than 2 kg – 75 mg/kg every 12 hours, for premature infants weighing more than 2 kg – 75 mg/kg every 8 hours.

Elderly patients do not require dose adjustment.

For adults and children weighing more than 40 kg with renal impairment the drug is prescribed in the following doses.

Creatinine clearance Dosage regimen
>60 ml/min 3 g every 4 h
30-60 ml/min 2 g every 4 h or 3 g every 8 h
10-30 ml/min 2 g every 8 h or 3 g every 12 h
<10 ml/min 1 g every 6 h or 2 g every 12 h or 3 g every 24 h
<10 ml/min (with concomitant hepatic impairment) 1 g every 12 h or 2 g every 24 h
Patients on peritoneal dialysis 1 g every 6 h or 2 g every 12 h or 3 g every 24 h
Patients on hemodialysis 1 g every 6 h or 2 g every 12 h or 3 g every 24 h, adding 3 g each time after dialysis

For children weighing less than 40 kg with renal impairment the drug is prescribed in the following doses.

Creatinine clearance Dosage regimen
>30 ml/min 75 mg/kg every 8 h
10-30 ml/min 37.5 mg/kg every 8 h
<10 ml/min 37.5 mg/kg every 12 h

There are no precise data for dosage regimen recommendations in premature newborns with renal impairment.

There are no precise data for dosage regimen recommendations in hepatic impairment.

Rules for preparation and administration of solutions

To prepare a solution for IV drip infusion, it is recommended to use water for injections or a dextrose (glucose) solution for IV infusion not exceeding 5% as a solvent. The sterile powder in vials of 1.6 g or 3.2 g is dissolved in approximately 10 ml of solvent before dilution in infusion containers. After that, it is recommended to use the following volumes of solvents.

Amount of drug in vial Water for injections Dextrose (glucose) solution for IV infusion not exceeding 5%
1.6 g 50 ml 100 ml
3.2 g 100 ml 100-150 ml

Each dose of Timentin is administered by IV drip over 30-40 minutes. Administration over a longer period is not recommended, as this may lead to subtherapeutic concentrations of the drug, reducing its efficacy.

To prepare a solution for IV bolus injection, the sterile powder is dissolved in 10 ml (vial 1.6 g) or 20 ml (vial 3.2 g) of water for injections. The solution is administered slowly as a bolus over 3-4 minutes. Timentin can be administered directly into a vein or through a drip line.

When Timentin is dissolved, heat is released. The prepared solution usually has a light straw color.

Any unused solution after administration is not suitable for further use.

The infusion solution is recommended to be prepared immediately before use; nevertheless, the following Timentin infusion solutions remain stable at 25°C (77°F) for the periods of time indicated below:

Solvent Stability period
Water for injections 24 h
Dextrose (glucose) solution for IV infusion (5%) 12 h
Sodium chloride (0.18%) and glucose (4%) solutions for IV infusion 24 h
Sodium chloride solution for IV infusion (0.9%) 24 h
Dextran 40 for IV infusion (10%) in dextrose (glucose) solution for IV infusion (5%) 6 h
Dextran 40 for IV infusion (10%) in sodium chloride solution for IV infusion (0.9%) 24 h
Dextrose (glucose) solution for IV infusion (10%) 6 h
Sorbitol solution for IV infusion (30%) 6 h
Sodium lactate solution for IV infusion (M/6) 12 h
Combined sodium lactate solution for IV infusion (Ringer’s lactate solution, Hartmann’s solution) 12 h

Adverse Reactions

From the digestive system: nausea, vomiting, diarrhea; in very rare cases – pseudomembranous colitis.

From the hepatobiliary system: moderate increase in AST and/or ALT in patients receiving ampicillin-class antibiotics; very rarely – hepatitis and cholestatic jaundice. These phenomena have also been observed with the use of other penicillin and cephalosporin antibiotics.

From the CNS: rarely – seizures (in patients with impaired renal function and when high doses of the drug are prescribed).

From the hematopoietic system: rarely – thrombocytopenia, leukopenia, eosinophilia, decreased hemoglobin level.

From the blood coagulation system: rarely – prolongation of prothrombin time and bleeding time. Increased bleeding is possible.

Allergic reactions: skin rash, itching, urticaria, anaphylactic reactions; very rarely – bullous reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

If any hypersensitivity reactions occur, the use of Timentin should be discontinued.

Local reactions: pain, burning sensation, redness and induration at the injection site, and thrombophlebitis upon intravenous administration.

Other: rarely – hypokalemia.

Contraindications

  • Premature infants with impaired renal function;
  • Hypersensitivity to beta-lactam antibiotics (including penicillins and cephalosporins).

Very rarely, the development of hypokalemia has been reported during the use of the drug. Therefore, caution is necessary when prescribing to patients with electrolyte or fluid imbalance. Periodic monitoring of serum potassium concentration is recommended for patients receiving the drug long-term.

Some patients treated with Timentin experienced a moderate increase in ALT and AST. In this regard, Timentin should be prescribed with caution to patients with severe hepatic impairment.

Use in Pregnancy and Lactation

No teratogenic effects of the drug were found in animal studies. There is limited data on its use during pregnancy. The decision to prescribe the drug during pregnancy should be made with particular caution. Therefore, when prescribing Timentin to pregnant women, the physician should carefully weigh the potential benefit and potential risk associated with the use of this drug.

Timentin can be prescribed during breastfeeding, but, considering that trace amounts of the drug pass into breast milk, the risk of sensitization in the newborn should be taken into account.

Use in Hepatic Impairment

There are no precise data for dosage regimen recommendations in hepatic impairment.

Use in Renal Impairment

For adults and children weighing more than 40 kg with renal impairment, the drug is prescribed in the following doses.

Creatinine clearance Dosage regimen
>60 ml/min 3 g every 4 h
30-60 ml/min 2 g every 4 h or 3 g every 8 h
10-30 ml/min 2 g every 8 h or 3 g every 12 h
<10 ml/min 1 g every 6 h or 2 g every 12 h or 3 g every 24 h
<10 ml/min (with concomitant hepatic impairment) 1 g every 12 h or 2 g every 24 h
Patients on peritoneal dialysis 1 g every 6 h or 2 g every 12 h or 3 g every 24 h
Patients on hemodialysis 1 g every 6 h or 2 g every 12 h or 3 g every 24 h, adding 3 g after each dialysis session

For children weighing less than 40 kg with renal impairment, the drug is prescribed in the following doses.

Creatinine clearance Dosage regimen
>30 ml/min 75 mg/kg every 8 h
10-30 ml/min 37.5 mg/kg every 8 h
<10 ml/min 37.5 mg/kg every 12 h

There are no precise data for dosage regimen recommendations in premature newborns with impaired renal function.

Pediatric Use

Use is possible according to indications and in doses considering age.

Geriatric Use

Elderly patients do not require dose adjustment.

Special Precautions

Since serious, and in some cases fatal, hypersensitivity reactions (including anaphylactic reactions) have been observed in patients who previously received beta-lactam antibiotics, it is necessary to accurately establish the absence of such reactions in the medical history before prescribing Timentin. If allergic reactions occur, the use of the drug should be discontinued and supportive therapy should be provided; the development of anaphylactic reactions requires emergency measures according to accepted protocols.

Although Timentin has low toxicity characteristic of penicillin antibiotics, during long-term therapy it is recommended to periodically assess renal, hepatic, and hematopoietic function.

Increased bleeding has been observed in patients receiving beta-lactam antibiotics. Such reactions may be associated with impaired coagulation, platelet aggregation, and prolonged prothrombin time (primarily in patients with renal failure). If bleeding develops, the drug should be discontinued and appropriate therapeutic measures taken.

When prescribing Timentin to patients on a salt-free diet, the sodium content in the drug formulation should be taken into account.

Prolonged use of the drug may lead to the growth of non-susceptible strains of the pathogen.

When treating mixed infections caused by strains sensitive to ticarcillin (including beta-lactamase-producing strains), additional prescription of other antibiotics is not required.

To ensure adequate therapy, appropriate tests for pathogen susceptibility to the antibiotic should be performed. However, given the broad spectrum of bactericidal activity against gram-positive and gram-negative strains, the combination of ticarcillin and clavulanic acid is used as first-line therapy for mixed infections until the pathogen is identified. The combination of ticarcillin and clavulanic acid administered as monotherapy for some severe infections, which are usually treated with antibiotic combinations, has been shown to be effective. In vitro test results have shown a synergistic effect of aminoglycosides and the combination of ticarcillin with clavulanic acid against certain strains of Pseudomonas aeruginosa, suggesting the effectiveness of such combination therapy (especially in immunocompromised patients). In this case, both drugs should be prescribed at the recommended therapeutic doses. After obtaining the susceptibility test results, therapy should be adjusted if necessary.

Overdose

Symptoms: nausea, vomiting, diarrhea. The development of fluid volume and electrolyte imbalance is also possible. In case of overdose, some patients may develop increased neuromuscular excitability and convulsive seizures.

Treatment: if clinical signs of drug overdose develop, symptomatic therapy is indicated. In case of overdose, Ticarcillin and Clavulanic acid can be removed from the bloodstream by hemodialysis.

Drug Interactions

Concomitant use with probenecid is not recommended. Probenecid reduces the tubular secretion of ticarcillin. Simultaneous use with probenecid leads to a slowdown in the excretion of ticarcillin but does not affect the excretion of clavulanic acid.

Timentin exhibits synergism with aminoglycosides against a number of microorganisms, including Pseudomonas aeruginosa. Therefore, it is recommended to prescribe Timentin in combination with aminoglycosides for the treatment of life-threatening infections, especially in patients with impaired immunity. In this case, the specified drugs are administered separately at the recommended doses.

Clavulanic acid may cause nonspecific binding of IgG and albumin to erythrocyte membranes, leading to false-positive Coombs test results.

Like other antibiotics, Ticarcillin can alter the composition of the intestinal flora, leading to low estrogen reabsorption and, consequently, reduced effectiveness of combined oral contraceptives.

Pharmaceutical interaction

When Timentin is used in combination with aminoglycosides, the antibiotics should not be mixed in the same syringe, containers, or IV infusion systems, as this may lead to a decrease in the activity of the aminoglycosides.

Timentin is not sufficiently stable in infusion fluids containing bicarbonate.

It is not recommended to mix Timentin with blood products and other protein-like fluids, such as protein hydrolysates, as well as with intravenous lipid emulsions.

Storage Conditions

The drug should be stored out of the reach of children at a temperature from 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer

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