Timentin 0.8 G, 1.6 G, 3.2 G

1. Name Of The Medicinal Product

Timentin® 0.8 G, 1.6 G, 3.2 G

2. Qualitative And Quantitative Composition

Timentin 0.8 g: Contains 50 mg clavulanic acid with 750 mg ticarcillin.

Timentin 1.6 g: Contains 100 mg clavulanic acid with 1.5 g ticarcillin.

Timentin 3.2 g: Contains 200 mg clavulanic acid with 3.0 g ticarcillin.

The clavulanic acid is present as Potassium Clavulanate BP and the ticarcillin as ticarcillin sodium.

3. Pharmaceutical Form

Powder for solution for infusion.

Vials containing sterile powder for reconstitution.

4. Clinical Particulars

4.1 Therapeutic Indications

Timentin is an injectable antibiotic agent with a broad spectrum of bactericidal activity against a wide range of Gram-positive and Gram-negative aerobic and anaerobic bacteria. The presence of clavulanate in the formulation extends the spectrum of activity of ticarcillin to include many β-lactamase-producing bacteria normally resistant to ticarcillin and other β-lactam antibiotics.

Timentin is indicated for the treatment of infections in which susceptible organisms have been detected or are suspected.

Typical indications include:

Severe infections in hospitalised patients and proven or suspected infections in patients with impaired or suppressed host defences including: septicaemia, bacteraemia, peritonitis, intra-abdominal sepsis, post-surgical infections, bone and joint infections, skin and soft tissue infections, respiratory tract infections, serious or complicated renal infections (e.g. pyelonephritis), ear, nose and throat infections.

A comprehensive list of sensitive and resistant organisms is provided in Section 5.1. Consideration should be given to official guidance regarding bacterial resistance and the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Adult dosage (including elderly patients):

The usual dosage is 3.2 g Timentin given six to eight hourly. The maximum recommended dosage is 3.2 g four hourly.

Children's dosage (including infants, neonates and premature infants >2 kg in weight):

The usual dosage for children is 80 mg Timentin/kg body weight given every eight hours. The maximum dosage for children is 80 mg Timentin/kg body weight given every six hours. This should not exceed the maximum recommended adult dosage.

For premature infants <2 kg in weight, the dosage is 80 mg Timentin/kg body weight every 12 hours.

Dosage in renal impairment:

Mild impairment	Moderate impairment	Severe impairment
(Creatinine Clearance >30 ml/min)	(Creatinine Clearance 10-30 ml/min)	(Creatinine Clearance <10 ml/min)
3.2 g 8 hourly	1.6 g 8 hourly	1.6 g 12 hourly

Similar reductions in dosage should be made for children.

Administration:

Intravenous infusion

4.3 Contraindications

Timentin contains ticarcillin which is a penicillin, and should not be given to patients with a history of hypersensitivity to beta-lactam antibiotics (e.g. penicillins and cephalosporins).

4.4 Special Warnings And Precautions For Use

Before initiating therapy with Timentin, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactams (e.g. penicillins and cephalosporins). Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity.

Changes in liver function tests have been observed in some patients receiving Timentin. The clinical significance of these changes is uncertain but Timentin should be used with care in patients with evidence of severe hepatic dysfunction.

In patients with renal impairment, dosage should be adjusted according to the degree of impairment (see Section 4.2).

It should be noted that each gram of ticarcillin contains 5.3 mmol of sodium (approx.). This should be included in the daily allowance of patients on sodium restricted diets.

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.

Bleeding manifestations have occurred in some patients receiving beta-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, Timentin treatment should be discontinued and appropriate therapy instituted.

The presence of clavulanic acid in Timentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Timentin acts synergistically with aminoglycosides against a number of organisms including Pseudomonas. Timentin prescribed concurrently with an aminoglycoside, may therefore be preferred in the treatment of life-threatening infections, particularly in patients with impaired host defences. In such instances the two products should be administered separately, at the recommended dosages.

Co-administration of probenecid cannot be recommended. Probenecid decreases the renal tubular secretion of ticarcillin. Concurrent administration of probenecid delays ticarcillin renal excretion but does not delay the excretion of clavulanic acid.

The presence of clavulanic acid in Timentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

In common with other antibiotics, Timentin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. Therefore, alternative non-hormonal methods of contraception are recommended.

Penicillins reduce the excretion of methotrexate (potential increase in toxicity).

4.6 Pregnancy And Lactation

Pregnancy:

Animal studies with Timentin have shown no teratogenic effects. Penicillins are generally considered safe for use in pregnancy. Limited information is available concerning the results of the use of Timentin in human pregnancy. The decision to administer any drug during pregnancy should be taken with the utmost care. Therefore Timentin should only be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Lactation:

Trace quantities of Timentin are excreted in breast milk.

Timentin may be administered during the period of lactation. With the exception of the risk of sensitization, there are no detrimental effects for the breast-fed infant.

4.7 Effects On Ability To Drive And Use Machines

Adverse effects on the ability to drive or operate machinery have not been observed.

4.8 Undesirable Effects

Hypersensitivity reactions:

Hypersensitivity effects, including skin rashes:

Skin rashes, pruritus, urticaria, and anaphylactic reactions.

Bullous reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported very rarely.

Gastrointestinal effects:

Nausea, vomiting and diarrhea have been reported. Pseudomembranous colitis has been reported rarely.

Hepatic effects:

A moderate rise in AST and/or ALT has been noted in patients receiving ampicillin class antibiotics. Hepatitis and cholestatic jaundice have been reported very rarely. These events have been noted with other penicillins and cephalosporins.

Renal and urinary effects:

Hypokalaemia has been reported rarely. Haemorrhagic cystitis has been reported very rarely.

Central Nervous System effects:

Convulsions may occur rarely, particularly in patients with impaired renal function or in those receiving high doses.

Haematological effects:

Thrombocytopenia, leukopenia, eosinophilia and reduction of haemoglobin have been reported rarely. Haemolytic anaemia has been reported very rarely. Prolongation of prothrombin time and bleeding time. Bleeding manifestations have occurred.

Local effects:

Pain, burning, swelling and induration at the injection site and thrombophlebitis with intravenous administration.

4.9 Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically.

Disturbances of the fluid and electrolyte balances may be evident and may be treated symptomatically.

Ticarcillin and clavulanic acid may be removed from circulation by haemodialysis.

As with other penicillins, Timentin overdosage has the potential to cause neuromuscular hyperirritability or convulsive seizures.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Timentin is an injectable antibiotic, active against a wide range of both Gram-positive and Gram-negative bacteria, including β-lactamase-producing strains.

Resistance to many antibiotics is caused by bacterial enzymes which destroy the antibiotic before it can act on the pathogen. The clavulanate in Timentin anticipates this defence mechanism by blocking the β-lactamase enzymes, thus rendering the organisms sensitive to ticarcillin's rapid bactericidal effect at concentrations readily attainable in the body.

Clavulanate, by itself, has little antibacterial effect; however, in association with ticarcillin, as Timentin it produces an antibiotic agent with a breadth of spectrum suitable for empiric use in a wide range of infections treated parenterally in hospital.

Gram-Positive

Aerobes: Staphylococcus species including Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus species including Enterococcus faecalis.

Anaerobes: Peptococcus species, Peptostreptococcus species, Clostridium species, Eubacterium species.

Gram-Negative

Aerobes: Escherichia coli, Haemophilus species including Haemophilus influenzae, Moraxella catarrhalis, Klebsiella species including Klebsiella pneumoniae, Enterobacter species, Proteus species including indole-positive strains, Providentia stuartii, Pseudomonas species including Pseudomonas aeruginosa, Serratia species including Serratia marcescens, Citrobacter species, Acinetobacter species, Yersinia enterocolitica

Anaerobes: Bacteroides species including Bacteroides fragilis, Fusobacterium species, Veillonella species.

Breakpoints

The breakpoints listed below have been obtained from the National Committee for Clinical Laboratory Standards (NCCLS) (Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - Seventh Edition).

Enterobacteriaceae	S	R
Pseudomonas aeruginosa	S	R
Other non-Enterobacteriaceae	S	R
Staphylococcus spp.	S	R

S = susceptible, R = resistant

There are no NCCLS breakpoints for other organisms listed in this document.

Table 1

Susceptible Aerobic Gram-positive micro-organisms Staphylococcus aureus Aerobic Gram-negative micro-organisms Acinetobacter species Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Proteus species Serratia species Anaerobic micro-organisms Bacteroides fragilis

Intermediate Aerobic Gram-negative micro-organisms Serratia marcescens

Insusceptible Aerobic Gram-positive micro-organisms Enterococcus Aerobic Gram-negative micro-organisms Citrobacter species Enterobacter species Pseudomonas aeruginosa

The prevalence of resistance may vary geographically and with time for selected species. Where possible, local information on resistance is included. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to ticarcillin disodium clavulanate potassium (commonly known as Timentin) or not.

5.2 Pharmacokinetic Properties

The pharmacokinetics of the two components are closely matched and both components are well distributed in body fluids and tissues. Both clavulanate and ticarcillin have low levels of serum binding; about 20% and 45% respectively.

As with other penicillins the major route of elimination for ticarcillin is via the kidney; clavulanate is also excreted by this route.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None

6.2 Incompatibilities

Timentin is not compatible with the following:

Proteinaceous fluids (e.g. protein hydrolysates); blood and plasma; intravenous lipids.

If Timentin is prescribed concurrently with an aminoglycoside the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Timentin should be stored in a dry place at temperatures below 25°C.

6.5 Nature And Contents Of Container

Clear Type I or Type III glass vials fitted with a chlorobutyl rubber bung and an aluminium seal. Supplied in packs of four vials.

6.6 Special Precautions For Disposal And Other Handling

The sterile powder should be dissolved in approximately 5 ml/10 ml (1.6 g/3.2 g vial) prior to dilution into the infusion container (e.g. mini-bag) or in-line burette.

The following approximate infusion volumes are suggested:

	Water for Injections BP	Glucose Intravenous Infusion BP (5% w/v)
3.2 g	100 ml	100-150 ml
1.6 g	50 ml	100 ml

Detailed instructions are given in the Package Enclosure Leaflet.

Each dose of Timentin should be infused intravenously over a period of 30-40 minutes; avoid continuous infusion over longer periods as this may result in subtherapeutic concentrations.

800 mg Timentin has a displacement value of 0.55 ml.

Heat is generated when Timentin dissolves. Reconstituted solutions are normally a pale straw colour.

Timentin presentations are not for multi-dose use or for direct IV or IM injection. Any residual antibiotic solution should be discarded if less than the fully made up vial is used.

Administrative Data

7. Marketing Authorisation Holder

Beecham Group plc, Great West Road

Brentford, Middlesex TW8 9GS

Trading as:

GlaxoSmithKline UK,

Stockley Park West,

Uxbridge,

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

00038/0329

9. Date Of First Authorisation/Renewal Of The Authorisation

15 April 2003

10. Date Of Revision Of The Text

03 October 2011

11. LEGAL STATUS

POM