SUMMARY OF PRODUCT CHARACTERISTICS

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 1.6g: 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 indicated for the treatment of infections in which susceptible organisms have been detected or are suspected.

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

The dosing below is based on the ticarcillin content.

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.

Renal impairment - Adults and children over 40 kg

An initial loading dose of 3 g should be followed by doses based on creatinine clearance rate and type of dialysis as indicated below:

-    Creatinine clearance greater than 60 ml/minute: 3 g every 4 hours OR 5g every 6 hours

-    Creatinine clearance 30 to 60 ml/minute: 2 g every 4 hours OR 3g every 8 hours

-    Creatinine clearance 10 to 30 ml/minute: 2 g every 8 hours OR 3 g every 12 hours

-    Creatinine clearance less than 10 ml/minute: 1 g i.m. every 6 hours OR 2 g every 12 hours OR 3 g every 24 hours

-    Creatinine clearance less than 10 ml/minute (with hepatic dysfunction): 1 g i.m. every 12 hours OR 2 g every 24 hours

-    Patients on peritoneal dialysis: as for creatinine clearance less than 10 ml/minute

-    Patients on haemodialysis: as for creatinine clearance less than 10 ml/minute supplemented with 3 g after each dialysis.

Renal impairment - Children under 40 kg

Similar dosage adjustment as for adults, e.g. an initial loading dose of 75 mg/kg should be followed by doses based on creatinine clearance and type of dialysis as indicated below:

- Greater than 30 ml/minute:    75 mg/kg every 8 hours

- 10 to 30 ml/minute:    37.5 mg/kg every 8 hours

Administration:

Intravenous infusion

4.3 Contra-Indications

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 100 mg of sodium (approx.). The theoretical potassium content is 0.3 mEq (11.9 mg). This should be included in the daily allowance of patients on sodium or potassium 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.

Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further.

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 sensitisation, 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, 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 (see Warnings and Precautions).

Hepatic effects:

A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics but the significance of these findings is unknown. 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, leucopenia and eosinophilia have been reported rarely and reduction of haemoglobin. 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors

ATC code: J01CR03 Mechanism of Action

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 derived from the basic penicillin nucleus, 6-amino-penicillanic acid.

Ticarcillin is, however, susceptible to degradation by beta-lactamases and therefore the spectrum of activity does not normally include organisms which produce these enzymes.

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

The formulation of ticarcillin with clavulanic acid in ticarcillin-clavulanate protects ticarcillin from degradation by beta-lactamase enzymes and effectively extends the antibiotic spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other beta-lactam antibiotics.

Thus ticarcillin-clavulanate possesses the distinctive properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.

Mechanism of Resistance

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 □-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.

Timentin Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Microorganism	Breakpoints (mg/L)
	S (<)	R (>)
Enterobacteriaceae	81	161
Pseudomonas spp.	161	161
Anaerobes	81	161
Staphylococcus spp.	Note2	Note2
Haemophilus influenzae	IE3	IE3
Moraxella catarrhalis	IE3	IE3

Eubacterium spp.

Peptostreptococcus spp.|

Gram-negative anaerobes:

Bacteroides spp. including B. fragilis Prevotella spp.

Fusobacterium spp.

Microorganisms for which acquired resistance may be a problem

Gram-positive aerobes:

Streptococcus pneumoniae^

Viridans group streptococci^

Gram-negative aerobes:

Acinetobacter spp.

Citrobacter spp.

Enterobacter spp.

Escherichia coli Haemophilus influenzae Klebsiella spp.

Morganella morganii Neisseria gonorrhoeae Proteus spp.

Providencia spp.

Pseudomonas spp. including Pseudomonas aeruginosa Serratia spp.

Salmonella spp.

Gram-negative anaerobes:

Veillonella spp.

Inherently resistant microorganisms ^{2 1} 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    Pre-clinical 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; sodium bicarbonate.

Timentin solutions containing lidocaine hydrochloride should not be used for intravenous administration.

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. Do not store above 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. Instructions for Use, Handling and Disposal

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)

3.2g    100ml    100-150ml

1.6g    50ml    100ml

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.

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 Or

Beecham Research or Bencard or Bridge Pharmaceuticals or SmithKline and French

Laboratories or SmithKline Beecham Pharmaceuticals all at: Welwyn Garden City, Hertfordshire AL7 1EY

8.    MARKETING AUTHORISATION NUMBER(S)

PL 00038/0329

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15 April 2003

10 DATE OF REVISION OF THE TEXT

27/03/2014

1

All methicillin-resistant Staphylococcus spp. are resistant to Timentin.

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

2

Stenotrophomonas maltophilia Burkholderia cepacia