Biotum

Biotum is indicated for the treatment of the infections listed below in adults and children including neonates (from birth).

- Nosocomial pneumonia

- Broncho-pulmonary infections in cystic fibrosis

- Bacterial meningitis

- Chronic suppurative otitis media

- Malignant otitis externa

- Complicated urinary tract infections

- Complicated skin and soft tissue infections

- Complicated intra-abdominal infections

- Bone and joint infections

- Peritonitis associated with dialysis in patients on CAPD.

Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Biotum may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

Biotum may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing trans-urethral resection of the prostate (TURP).

The selection of Biotum should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram negative bacteria.

Biotum should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum of activity.

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

Posology

Table 1: Adults and children > 40 kg

Table 2: Children < 40 kg

Paediatric population

The safety and efficacy of Biotum administered as continuous infusion to neonates and infants ≤ 2 months has not been established.

Elderly

In view of age related reduced clearance of Biotum in elderly patients, the daily dose should not normally exceed 3 g in those over 80 years of age.

Hepatic impairment

Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment.). Close clinical monitoring for safety and efficacy is advised.

Renal impairment

Biotum is excreted unchanged by the kidneys.).

An initial loading dose of 1 g should be given. Maintenance doses should be based on creatinine clearance:

Table 3: Recommended maintenance doses of Biotum in renal impairment - intermittent infusion

Adults and children > 40 kg

In patients with severe infections the unit dose should be increased by 50% or the dosing frequency increased.

In children the creatinine clearance should be adjusted for body surface area or lean body mass.

Children < 40 kg

Close clinical monitoring for safety and efficacy is advised.

Table 4: Recommended maintenance doses of Biotum in renal impairment - continuous infusion

Adults and children > 40 kg

Caution is advised in dose selection. Close clinical monitoring for safety and efficacy is advised.

Children < 40 kg

The safety and effectiveness of Biotum administered as continuous infusion in renally impaired children < 40 kg has not been established. Close clinical monitoring for safety and efficacy is advised.

If continuous infusion is used in children with renal impairment, the creatinine clearance should be adjusted for body surface area or lean body mass.

Haemodialysis

The serum half-life during haemodialysis ranges from 3 to 5 h.

Following each haemodialysis period, the maintenance dose of Biotum recommended in the below table should be repeated.

Peritoneal dialysis

Biotum may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD).

In addition to intravenous use, Biotum can be incorporated into the dialysis fluid (usually 125 to 250 mg for 2 litres of dialysis solution).

For patients in renal failure on continuous arterio-venous haemodialysis or high-flux haemofiltration in intensive therapy units: 1 g daily either as a single dose or in divided doses. For low-flux haemofiltration, follow the dose recommended under renal impairment.

For patients on veno-venous haemofiltration and veno-venous haemodialysis, follow the dosage recommendations in the tables 5 & 6 below.

Table 5: Continuous veno-venous haemofiltration dose guidelines

Table 6: Continuous veno-venous haemodialysis dose guidelines

Method of administration

The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.

Biotum should be administered by intravenous injection or infusion, or by deep intramuscular injection. Recommended intramuscular injection sites are the upper outer quadrant of the gluteus maximus or lateral part of the thigh. Biotum solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids.

The standard recommended route of administration is by intravenous intermittent injection or intravenous continuous infusion. Intramuscular administration should only be considered when the intravenous route is not possible or less appropriate for the patient.

History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).

Hypersensitivity

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with Biotum must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to Biotum, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if Biotum is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Spectrum of activity

Biotum has a limited spectrum of antibacterial activity. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with Biotum. This particularly applies when considering the treatment of patients with bacteraemia and when treating bacterial meningitis, skin and soft tissue infections and bone and joint infections. In addition, Biotum is susceptible to hydrolysis by several of the extended spectrum beta lactamases (ESBLs). Therefore information on the prevalence of ESBL producing organisms should be taken into account when selecting Biotum for treatment.

Pseudomembranous colitis

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including Biotum, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of Biotum. Discontinuation of therapy with Biotum and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Renal function

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.

Biotum is eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and efficacy. Neurological sequelae have occasionally been reported when the dose has not been reduced in patients with renal impairment.

Overgrowth of non-susceptible organisms

Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. Enterococci, fungi) which may require interruption of treatment or other appropriate measures. Repeated evaluation of the patient's condition is essential.

Test and assay interactions

Biotum does not interfere with enzyme-based tests for glycosuria, but slight interference (false-positive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).

Biotum does not interfere in the alkaline picrate assay for creatinine.

The development of a positive Coombs' test associated with the use of Biotum in about 5% of patients may interfere with the cross-matching of blood.

Sodium content

Important information about one of the ingredients of Biotum:

1 g powder for solution for injection or infusion, 1 g powder for solution for infusion

Biotum 1 g contains 2.26mmol of sodium per vial.

This should be considered for patients who are on a controlled sodium diet.

No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines.

The most common adverse reactions are eosinophilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or urticarcial rash, pain and/or inflammation following intramuscular injection and positive Coomb's test.

Data from sponsored and un-sponsored clinical trials have been used to determine the frequency of common and uncommon undesirable effects. The frequencies assigned to all other undesirable effects were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following convention has been used for the classification of frequency:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Unknown (cannot be estimated from the available data)

1There have been reports of neurological sequelae including tremor, myoclonia, convulsions, encephalopathy and coma in patients with renal impairment in whom the dose of Biotum has not been appropriately reduced.

2 Diarrhoea and colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.

3 ALT (SGPT), AST (SOGT), LHD, GGT, alkaline phosphatase.

4 There have been rare reports where DRESS has been associated with Biotum.

5 A positive Coombs test develops in about 5% of patients and may interfere with blood cross matching.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Overdose can lead to neurological sequelae including encephalopathy, convulsion and coma.

Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.

Serum levels of Biotum can be reduced by haemodialysis or peritoneal dialysis.

Pharmacotherapeutic group: Antibacterials for systemic use. Third-generation cephalosporins ATC code: J01DD02.

Mechanism of action

Biotum inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

PK/PD relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of Biotum for individual target species (i.e. %T>MIC).

Mechanism of Resistance

Bacterial resistance to Biotum may be due to one or more of the following mechanisms:

- hydrolysis by beta-lactamases. Biotum may be efficiently hydrolysed by extended spectrum beta-lactamases (ESBLs), including the SHV family of ESBLs, and AmpC enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species

- reduced affinity of penicillin-binding proteins for Biotum

- outer membrane impermeability, which restricts access of Biotum to penicillin binding proteins in Gram-negative organisms.

- bacterial efflux pumps.

Breakpoints

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

S=susceptible, I=intermediate, R=resistant.

1The breakpoints relate to high dose therapy (2 g x 3).

2Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes.

Microbiological Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of Biotum in at least some types of infections is questionable

Absorption

After intramuscular administration of 500 mg and 1 g of Biotum, peak plasma levels of 18 and 37 mg/l, respectively, are achieved rapidly. Five minutes after intravenous bolus injection of 500 mg, 1 g or 2 g, plasma levels are 46, 87 and 170 mg/l, respectively. The kinetics of Biotum are linear within the single dose range of 0.5 to 2 g following intravenous or intramuscular dosing.

Distribution

The serum protein binding of Biotum is low at about 10%. Concentrations in excess of the MIC for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, synovial, pleural and peritoneal fluids. Biotum crosses the placenta readily, and is excreted in the breast milk. Penetration of the intact blood-brain barrier is poor, resulting in low levels of Biotum in the CSF in the absence of inflammation. However, concentrations of 4 to 20 mg/l or more are achieved in the CSF when the meninges are inflamed.

Biotransformation

Biotum is not metabolised.

Elimination

After parenteral administration plasma levels decrease with a half-life of about 2 h. Biotum is excreted unchanged into the urine by glomerular filtration; approximately 80 to 90% of the dose is recovered in the urine within 24 h. Less than 1% is excreted via the bile.

Special patient populations

Renal impairment

Elimination of Biotum is decreased in patients with impaired renal function and the dose should be reduced.

Hepatic impairment

The presence of mild to moderate hepatic dysfunction had no effect on the pharmacokinetics of Biotum in individuals administered 2 g intravenously every 8 hours for 5 days, provided renal function was not impaired.

Elderly

The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of Biotum. The mean elimination half-life ranged from 3.5 to 4 hours following single or 7 days repeat BID dosing of 2 g IV bolus injections in elderly patients 80 years or older.

Paediatric population

The half-life of Biotum is prolonged in preterm and term neonates by 4.5 to 7.5 hours after doses of 25 to 30 mg/kg. However, by the age of 2 months the half-life is within the range for adults.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeat dose toxicity, genotoxicity, toxicity to reproduction. Carcinogenicity studies have not been performed with Biotum.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Biotum is less stable in Sodium Bicarbonate Injection than other intravenous fluids. It is not recommended as a diluent.

Biotum and aminoglycosides should not be mixed in the same giving set or syringe.

Precipitation has been reported when vancomycin has been added to Biotum in solution. Therefore, it would be prudent to flush giving sets and intravenous lines between administration of these two agents.

Biotum is incompatible with aminophylline. There is a possible incompatibility with pentamide.

For single use. Discard any unused contents.

Instructions for reconstitution: See table for addition volumes and solution concentrations, which may be useful when fractional doses are required.

PREPARATION OF SOLUTION

Biotum (at the given concentration) has been shown to be compatible with the following diluent solutions:-

Solvents for 40mg/ml Biotum concentration:

Sodium Chloride 0.9%

Ringer Solution

Ringer Lactate Solution

Glucose 5%

Glucose 10%

Glucose 5% and Sodium Chloride 0.9%

Glucose 5% and Sodium Chloride 0.45%

Glucose 5% and Sodium Chloride 0.2%

Dextran 40%/10% and Sodium Chloride 0.9%

Dextran 70%/6% and Sodium Chloride 0.9%

Lidocaine Hydrochloride 0.5%

Lidocaine Hydrochloride 1%

Solutions range from light yellow to amber depending on concentration, diluent and storage conditions used.

All sizes of vials as supplied are under reduced pressure. As the product dissolves, carbon dioxide is released and a positive pressure develops. For ease of use, it is recommended that the following technique of reconstitution is adopted.

1. Insert the syringe needle through the vial closure and inject the recommended volume of diluent. The vacuum may assist entry of the diluent. Remove the syringe needle.

2. Shake to dissolve: carbon dioxide is released and a clear solution will be obtained in about 1 to 2 minutes.

3. Invert the vial. With the syringe plunger fully depressed, insert the needle through the vial closure and withdraw the total volume of solution into the syringe (the pressure in the vial may aid withdrawal). Ensure that the needle remains within the solution and does not enter the head space. The withdrawn solution may contain small bubbles of carbon dioxide; they may be disregarded.

These solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parental fluids.