Orextil

Orextil is indicated for the treatment of the infections listed below in adults and children from the age of 3 months.

- Acute streptococcal tonsillitis and pharyngitis.

- Acute bacterial sinusitis.

- Acute otitis media.

- Acute exacerbations of chronic bronchitis.

- Cystitis.

- Pyelonephritis.

- Uncomplicated skin and soft tissue infections.

- Treatment of early Lyme disease.

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

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

- Community acquired pneumonia

- Acute exacerbations of chronic bronchitis

- Complicated urinary tract infections, including pyelonephritis

- Soft-tissue infections: cellulitis, erysipelas and wound infections

- Intra-abdominal infections

- Prophylaxis against infection in gastrointestinal (including oesophageal), orthopaedic, cardiovascular, and gynaecological surgery (including caesarean section)

In the treatment and prevention of infections in which it is very likely that anaerobic organisms will be encountered, cefuroxime should be administered with additional appropriate antibacterial agents.

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

Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery.

Consideration should be given to official guidance on the appropriate use of antibacterial agents, including guidance on the antibiotic prophylaxis on eye surgery.

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

- Community acquired pneumonia

- Acute exacerbations of chronic bronchitis

- Complicated urinary tract infections, including pyelonephritis

- Soft-tissue infections: cellulitis, erysipelas and wound infections

- Intra-abdominal infections

- Prophylaxis against infection in gastrointestinal (including oesophageal), orthopaedic, cardiovascular, and gynaecological surgery (including caesarean section)

In the treatment and prevention of infections in which it is very likely that anaerobic organisms will be encountered, cefuroxime should be administered with additional appropriate antibacterial agents.

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

Posology

The usual course of therapy is seven days (may range from five to ten days).

Table 1. Adults and children (>40 kg)

Table 2. Children (<40 kg)

There is no experience of using Orextil in children under the age of 3 months.

Cefuroxime axetil tablets and cefuroxime axetil granules for oral suspension are not bioequivalent and are not substitutable on a milligram-per-milligram basis.

In infants (from the age of 3 months) and children with a body mass of less than 40 kg, it may be preferable to adjust dosage according to weight or age. The dose in infants and children 3 months to 18 years is 10 mg/kg twice daily for most infections, to a maximum of 250 mg daily. In otitis media or more severe infections the recommended dose is 15 mg/kg twice daily to a maximum of 500 mg daily.

The following two tables, divided by age group, serve as a guideline for simplified administration, e.g measuring spoon (5 ml), for the 125 mg/5 ml or the 250 mg/5 ml multi-dose suspension if provided, and 125 mg or 250 mg single dose sachets.

Table 3. 10 mg/kg dosage for most infections

Table 4. 15 mg/kg dosage for otitis media and more serious infections

Renal impairment

The safety and efficacy of cefuroxime axetil in patients with renal failure have not been established. Cefuroxime is primarily excreted by the kidneys. In patients with markedly impaired renal function it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by dialysis.

Table 5. Recommended doses for Orextil in renal impairment

Hepatic impairment

There are no data available for patients with hepatic impairment. Since cefuroxime is primarily eliminated by the kidney, the presence of hepatic dysfunction is expected to have no effect on the pharmacokinetics of cefuroxime.

Method of administration

Oral use

For optimal absorption cefuroxime axetil suspension should be taken with food.

Depending on the dosage, there are other presentations available.

Posology

Table 1. Adults and children > 40 kg

Table 2.Children < 40 kg

Renal impairment

Cefuroxime is primarily excreted by the kidneys. Therefore, as with all such antibiotics, in patients with markedly impaired renal function it is recommended that the dosage of Cefuroxime should be reduced to compensate for its slower excretion.

Table 3. Recommended doses for Cefuroxime in renal impairment

Hepatic impairment

Cefuroxime is primarily eliminated by the kidney. In patients with hepatic dysfunction this is not expected to effect the pharmacokinetics of cefuroxime.

Method of administration

Cefuroxime should be administered by intravenous injection over a period of 3 to 5 minutes directly into a vein or via a drip tube or infusion over 30 to 60 minutes, or by deep intramuscular injection.

750 mg powder for solution for infusion.

Intracameral use. One vial for single-use only.

Posology

Adults:

The recommended dose is 0.1ml of reconstituted solution , i.e. 1mg of Orextil.

DO NOT INJECT MORE THAN THE RECOMMENDED DOSE.

Paediatric population:

The optimal dose and the safety of APROKAM have not been established in the paediatric population.

Elderly:

No dose adjustment is necessary.

Patients with hepatic and renal impairment:

Considering the low dose and the expected negligible systemic exposure to Orextil using APROKAM, no dose adjustment is necessary.

Method of administration

APROKAM must be administered after reconstitution by intraocular injection in the anterior chamber of the eye (intracameral use), by an ophthalmic surgeon, in the recommended aseptic conditions of cataract surgery.

After reconstitution, APROKAM should be inspected visually for particulate matter and discoloration prior to administration.

Slowly inject 0.1ml of the reconstituted solution into the anterior chamber of the eye at the end of the cataract surgery.

Posology

Table 1. Adults and children > 40 kg

Table 2. Children < 40 kg

Renal impairment

Cefuroxime is primarily excreted by the kidneys. Therefore, as with all such antibiotics, in patients with markedly impaired renal function it is recommended that the dosage of Orextil should be reduced to compensate for its slower excretion.

Table 3. Recommended doses for Orextil in renal impairment

Hepatic impairment

Cefuroxime is primarily eliminated by the kidney. In patients with hepatic dysfunction this is not expected to affect the pharmacokinetics of cefuroxime.

Method of administration

Orextil should be administered by intravenous injection over a period of 3 to 5 minutes directly into a vein or via a drip tube or infusion over 30 to 60 minutes, or by deep intramuscular injection.

Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than 750 mg should be injected at one site.

750 mg, 1.5 g powder for solution for infusion (Monovial presentation).

Patients with known hypersensitivity to cephalosporin antibiotics.

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

Patients with known hypersensitivity to cephalosporin antibiotics.

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

Hypersensitivity to Orextil or to the cephalosporin group of antibiotics.

Patients with known hypersensitivity to cephalosporin antibiotics.

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

Hypersensitivity reactions

Special care is indicated in patients who have experienced an allergic reaction to penicillins or other beta-lactam antibiotics because there is a risk of cross-sensitivity. As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime 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 cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction has been seen following cefuroxime axetil treatment of Lyme disease. It results directly from the bactericidal activity of cefuroxime axetil on the causative bacteria of Lyme disease, the spirochaete Borrelia burgdorferi. Patients should be reassured that this is a common and usually self-limiting consequence of antibiotic treatment of Lyme disease.

Overgrowth of non-susceptible microorganisms

As with other antibiotics, use of cefuroxime axetil may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment.

Antibacterial agent-associated pseudomembranous colitis have been reported with nearly all antibacterial agents, including cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime. Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Interference with diagnostic tests

The development of a positive Coomb's Test associated with the use of cefuroxime may interfere with cross matching of blood.

As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime axetil.

Important information about excipients

The sucrose content of cefuroxime axetil suspension and granules should be taken into account when treating diabetic patients and appropriate advice provided.

125mg/5ml granules for oral suspension:

Contains 3 g of sucrose per 5 ml dose

125mg granules for oral suspension:

Contains 3 g of sucrose per unit dose

Cefuroxime axetil suspension contains aspartame, which is a source of phenylalanine and so should be used with caution in patients with phenylketonuria.

Hypersensitivity reactions

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime 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 cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Cephalosporin antibiotics may, in general, be given safely to patients who are hypersensitive to penicillins, although cross-reactions have been reported. Special care is indicated in patients who have experienced an anaphylactic reaction to penicillin.

Concurrent treatment with potent diuretics or aminoglycosides

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide or aminoglycosides. Renal impairment has been reported during use of these combinations. Renal function should be monitored in the elderly and those with known pre-existing renal impairment.

Overgrowth of non-susceptible microorganisms

Use of cefuroxime may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment.

Antibacterial agent-associated pseudomembranous colitis has been reported with use of cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime. Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Intra-abdominal infections

Due to its spectrum of activity, cefuroxime is not suitable for the treatment of infections caused by Gram-negative non-fermenting bacteria.

Interference with diagnostic tests

The development of a positive Coombs Test associated with the use of cefuroxime may interfere with cross matching of blood.

Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed. However, this should not lead to false-positive results, as may be experienced with some other cephalosporins.

As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving Orextil.

Intracameral use and eye disorders

Cefuroxime is not formulated for intracameral use. Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intracameral use of Orextil compounded from vials approved for intravenous/intramuscular administration. These reactions included macular oedema, retinal oedema, retinal detachment, retinal toxicity, visual impairment, visual acuity reduced, vision blurred, corneal opacity and corneal oedema.

Important information about excipients

Cefuroxime powder for solution for injection and infusion contains sodium. This should be considered for patients who are on a controlled sodium diet.

Treatment with APROKAM is for intracameral use only.

Special care is indicated in patients who have experienced an allergic reaction to penicillins or any other beta-lactam antibiotics as cross-reactions may occur.

In patients at risk for infections with resistant strains, e.g. those with known previous infection or colonisation with MRSA (Methicillin-resistant Staphylococcus aureus), alternative prophylactic antibiotic should be considered.

In the absence of data for special patient groups (patients with severe risk of infection, patients with complicated cataracts, patients having combined operations with cataract surgery, patients with severe thyroid disease, patients with less 2000 corneal endothelial cells), APROKAM should only be used after careful risk/benefit assessment.

The use of Orextil should not be regarded as an isolated measure but other circumstances are also of importance like prophylactic antiseptic treatment.

Corneal endothelial toxicity has not been reported at the recommended concentration of Orextil; nevertheless, this risk cannot be excluded and in the post-surgical surveillance, physicians should have in mind this potential risk.

Hypersensitivity reactions

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefuroxime 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 cefuroxime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if cefuroxime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.

Concurrent treatment with potent diuretics or aminoglycosides

Cephalosporin antibiotics at high dosage should be given with caution to patients receiving concurrent treatment with potent diuretics such as furosemide or aminoglycosides. Renal impairment has been reported during use of these combinations. Renal function should be monitored in the elderly and those with known pre-existing renal impairment.

Overgrowth of non-susceptible microorganisms

Use of cefuroxime may result in the overgrowth of Candida. Prolonged use may also result in the overgrowth of other non-susceptible microorganisms (e.g. enterococci and Clostridium difficile), which may require interruption of treatment.

Antibacterial agent-associated pseudomembranous colitis has been reported with use of cefuroxime and may range in severity from mild to life threatening. This diagnosis should be considered in patients with diarrhoea during or subsequent to the administration of cefuroxime. Discontinuation of therapy with cefuroxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Intra-abdominal infections

Due to its spectrum of activity, cefuroxime is not suitable for the treatment of infections caused by Gram-negative non-fermenting bacteria.

Interference with diagnostic tests

The development of a positive Coomb's Test associated with the use of cefuroxime may interfere with cross matching of blood.

Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed. However, this should not lead to false-positive results, as may be experienced with some other cephalosporins.

As a false negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase methods are used to determine blood/plasma glucose levels in patients receiving cefuroxime sodium.

Important information about excipients

Orextil powder for solution for injection and infusion contains sodium. This should be considered for patients who are on a controlled sodium diet.

The most common adverse reactions are Candida overgrowth, eosinophilia, headache, dizziness, gastrointestinal disturbances and transient rise in liver enzymes.

The frequency categories assigned to the adverse reactions below are estimates, as for most reactions suitable data (for example from placebo-controlled studies) for calculating incidence were not available. In addition the incidence of adverse reactions associated with cefuroxime axetil may vary according to the indication.

Data from large clinical studies were used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e. those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than true frequency. Placebo-controlled trial data were not available. Where incidences have been calculated from clinical trial data, these were based on drug-related (investigator assessed) data. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Treatment related adverse reactions, all grades, are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised 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 and not known (cannot be estimated from the available data).

Paediatric population

The safety profile for cefuroxime axetil in children is consistent with the profile in adults.

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

The most common adverse reactions are neutropenia, eosinophilia, transient rise in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease, but there is no evidence of harm to the liver and injection site reactions.

The frequency categories assigned to the adverse reactions below are estimates, as for most reactions suitable data for calculating incidence are not available. In addition the incidence of adverse reactions associated with Orextil may vary according to the indication.

Data from clinical trials were used to determine the frequency of very common to rare adverse reactions. The frequencies assigned to all other adverse reactions (i.e. those occurring at <1/10,000) were mainly determined using post-marketing data, and refer to a reporting rate rather than a true frequency.

Treatment related adverse reactions, all grades, are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised 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 and not known (cannot be estimated from the available data).

Paediatric population

The safety profile for Orextil in children is consistent with the profile in adults.

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 - Website: www.mhra.gov.uk/yellowcard.

No particular adverse effects were reported in the literature when Orextil is administered as intraocular injection except the following:

Immune system disorders

Very rare (<1/10,000): Anaphylactic reaction.

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. Website: www.mhra.gov.uk/yellowcard

The most common adverse reactions are neutropenia, eosinophilia, transient rise in liver enzymes or bilirubin, particularly in patients with pre-existing liver disease, but there is no evidence of harm to the liver and injection site reactions.

The frequency categories assigned to the adverse reactions below are estimates, as for most reactions suitable data for calculating incidence are not available. In addition the incidence of adverse reactions associated with cefuroxime sodium may vary according to the indication.

Data from clinical trials were used to determine the frequency of very common to rare adverse reactions. The frequencies assigned to all other adverse reactions (i.e. those occurring at <1/10,000) were mainly determined using post-marketing data, and refer to a reporting rate rather than a true frequency.

Treatment related adverse reactions, all grades, are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised 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 and not known (cannot be estimated from the available data).

Paediatric population

The safety profile for cefuroxime sodium in children is consistent with the profile in adults.

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.

Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma. Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.

Serum levels of cefuroxime can be reduced by haemodialysis and peritoneal dialysis.

Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma. Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.

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

The reported cases of overdose are those described in the literature after incorrect dilution and non-authorised use of Orextil intended for systemic administration.

Inadvertent high-dose (3-fold the recommended dose) intracameral Orextil was administered to 6 patients following an incorrect dilution due to homemade Orextil dilution protocol. These injections did not cause any detectable adverse effect in any patient even on ocular tissues.

Toxicity data were available following intracameral injection, during cataract surgery, of 40 to 50-fold the recommended dose of Orextil in 6 patients after a dilution error. Initial mean visual acuity was 20/200. Severe anterior segment inflammation was present, and retinal optical coherence tomography showed extensive macular oedema. Six weeks after surgery, mean visual acuity reached 20/25. Macular optical coherence tomography profile returned to normal. A 30% decrease of scotopic electroretinography was, however, observed in all patients.

Administration of incorrectly diluted Orextil (10-100mg per eye) to 16 patients resulted in ocular toxicity including corneal oedema resolving in weeks, transient raised intraocular pressure, loss of corneal endothelial cells and changes in the electroretinography. A number of these patients had permanent and severe vision loss.

Overdose can lead to neurological sequelae including encephalopathy, convulsions and coma. Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.

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

Pharmacotherapeutic group: antibacterials for systemic use, second-generation cephalosporins, ATC code: J01DC02

Mechanism of action

Cefuroxime axetil undergoes hydrolysis by esterase enzymes to the active antibiotic, cefuroxime.

Cefuroxime 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.

Mechanism of resistance

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

- hydrolysis by beta-lactamases; including (but not limited to) by extended-spectrum beta-lactamases (ESBLs), and AmpC enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacteria species;

- reduced affinity of penicillin-binding proteins for cefuroxime;

- outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in Gram-negative bacteria;

- bacterial efflux pumps.

Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime.

Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime.

Cefuroxime axetil breakpoints

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

S=susceptible, R=resistant

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 cefuroxime axetil in at least some types of infections is questionable.

Cefuroxime is usually active against the following microorganisms in vitro.

*All methicillin-resistant S. aureus are resistant to cefuroxime.

Pharmacotherapeutic group: antibacterials for systemic use, Second-generation cephalosporins, ATC code: J01DC02

Mechanism of action

Cefuroxime 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.

Mechanism of resistance

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

- hydrolysis by beta-lactamases including (but not limited to) extended-spectrum beta-lactamases (ESBLs), and Amp-C enzymes, that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species;

- reduced affinity of penicillin-binding proteins for cefuroxime;

- outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in Gram-negative bacteria;

- bacterial efflux pumps.

Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime.

Orextil breakpoints

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

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 known and the utility of the agent in at least some types of infections is questionable.

Cefuroxime is usually active against the following microorganisms in vitro.

$ All methicillin-resistant S. aureus are resistant to cefuroxime.

In vitro the activities of Orextil and aminoglycoside antibiotics in combination have been shown to be at least additive with occasional evidence of synergy.

ATC classification

Pharmacotherapeutic group: Sensory Organs - Ophthalmologicals - Antiinfectives - Antibiotics

ATC code: S01AA27

Mechanism of action

Orextil 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.

PD/PK (pharmacodynamics/pharmacokinetics) 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 (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of Orextil for individual target species (i.e. %T>MIC).

After intracameral injection of 1 mg Orextil, Orextil levels in the aqueous humour were over MIC for several relevant species for up to 4- 5 hours after surgery.

Mechanism of resistance

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

- hydrolysis by beta-lactamases. Orextil may be efficiently hydrolysed by certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally-encoded (AmpC) enzyme that may be induced or stably derepressed in certain aerobic gram-negative bacterial species;

- reduced affinity of penicillin-binding proteins for Orextil;

- outer membrane impermeability, which restricts access of Orextil to penicillin binding proteins in gram-negative bacteria;

- bacterial drug efflux pumps.

Methicillin-resistant staphylococci (MRS) are resistant to all currently available β-lactam antibiotics including Orextil.

Penicillin-resistant Streptococcus pneumoniae are cross-resistant to cephalosporins such as Orextil through alteration of penicillin binding proteins.

Beta-lactamase negative, ampicillin resistant (BLNAR) strains of H. influenzae should be considered resistant to Orextil despite apparent in vitro susceptibility.

Breakpoints:

The list of micro-organisms presented hereafter has been targeted to the indication.

APROKAM should be used for intracameral application only and should not be used to treat systemic infections ; clinical breakpoints are not relevant for this route of administration. Epidemiological cut-off values (ECOFF), distinguishing the wild-type population from isolates with acquired resistance traits are as follows:

Susceptibility of staphylococci to Orextil is inferred from the methicillin susceptibility.

The susceptibility of streptococcus groups A, B, C and G can be inferred from their susceptibility to benzylpenicillin.

Information from clinical trials

An academic prospective randomized partially masked multicentre cataract surgery study was performed on 16,603 patients. Twenty-nine patients (24 in “without Orextil” groups and 5 in “intracameral Orextil” groups) presented with endophthalmitis, of whom 20 (17 in “without Orextil” groups and 3 in “intracameral Orextil” groups) were classified as having proven infective endophthalmitis. Among these 20 proven endophthalmitis: 10 patients are in group “placebo eye drops and without Orextil”, 7 patients in group “levofloxacine eye drops and without Orextil”, 2 patients in group “placebo eye drops and intracameral Orextil” and 1 patient in group “levofloxacine eye drops and intracameral Orextil. The administration of intracameral Orextil prophylactic regimen at 1mg in 0.1ml sodium chloride 9mg/ml (0.9%) solution for injection was associated with a 4.92-fold decrease in the risk for total postoperative endophthalmitis.

Two prospective studies (Wedje 2005 and Lundström 2007) and 5 retrospective studies were supportive to the pivotal ESCRS study further substantiating the efficacy of intracameral Orextil in postoperative endophthalmitis.

Pharmacotherapeutic group: antibacterials for systemic use, second-generation cephalosporins, ATC code: J01DC02

Mechanism of action

Cefuroxime 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.

Mechanism of resistance

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

- hydrolysis by beta-lactamases including (but not limited to) extended-spectrum beta-lactamases (ESBLs), and Amp-C enzymes, that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species;

- reduced affinity of penicillin-binding proteins for cefuroxime;

- outer membrane impermeability, which restricts access of cefuroxime to penicillin binding proteins in Gram-negative bacteria;

- bacterial efflux pumps.

Organisms that have acquired resistance to other injectable cephalosporins are expected to be resistant to cefuroxime. Depending on the mechanism of resistance, organisms with acquired resistance to penicillins may demonstrate reduced susceptibility or resistance to cefuroxime.

Cefuroxime sodium breakpoints

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

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 known and the utility of the agent in at least some types of infections is questionable.

Cefuroxime is usually active against the following microorganisms in vitro.

$ All methicillin-resistant S. aureus are resistant to cefuroxime.

In vitro the activities of cefuroxime sodium and aminoglycoside antibiotics in combination have been shown to be at least additive with occasional evidence of synergy.

Absorption

After oral administration cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolysed in the intestinal mucosa and blood to release cefuroxime into the circulation. Optimum absorption occurs when it is administered shortly after a meal.

Following administration of cefuroxime axetil tablets peak serum levels (2.1 mcg/ml for a 125 mg dose, 4.1 mcg/ml for a 250 mg dose, 7.0 mcg/ml for a 500 mg dose and 13.6 mcg/ml for a 1000 mg dose) occur approximately 2 to 3 hours after dosing when taken with food. The rate of absorption of cefuroxime from the suspension is reduced compared with the tablets, leading to later, lower peak serum levels and reduced systemic bioavailability (4 to 17% less). Cefuroxime axetil oral suspension was not bioequivalent to cefuroxime axetil tablets when tested in healthy adults and therefore is not substitutable on a milligram-per-milligram basis.The pharmacokinetics of cefuroxime is linear over the oral dosage range of 125 to 1000 mg. No accumulation of cefuroxime occurred following repeat oral doses of 250 to 500 mg.

Distribution

Protein binding has been stated as 33 to 50% depending on the methodology used. Following a single dose of cefuroxime axetil 500 mg tablet to 12 healthy volunteers, the apparent volume of distribution was 50 L (CV%=28%). Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum and aqueous humor. Cefuroxime passes the blood-brain barrier when the meninges are inflamed.

Biotransformation

Cefuroxime is not metabolised.

Elimination

The serum half-life is between 1 and 1.5 hours. Cefuroxime is excreted by glomerular filtration and tubular secretion. The renal clearance is in the region of 125 to 148 ml/min/1.73 m².

Special patient populations

Gender

No differences in the pharmacokinetics of cefuroxime were observed between males and females.

Elderly

No special precaution is necessary in the elderly patients with normal renal function at dosages up to the normal maximum of 1 g per day. Elderly patients are more likely to have decreased renal function; therefore, the dose should be adjusted in accordance with the renal function in the elderly.

Paediatrics

In older infants (aged >3 months) and in children, the pharmacokinetics of cefuroxime are similar to that observed in adults.

There is no clinical trial data available on the use of cefuroxime axetil in children under the age of 3 months.

Renal impairment

The safety and efficacy of cefuroxime axetil in patients with renal failure have not been established.

Cefuroxime is primarily excreted by the kidneys. Therefore, as with all such antibiotics, in patients with markedly impaired renal function (i.e. C1cr <30 ml/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by dialysis.

Hepatic impairment

There are no data available for patients with hepatic impairment. Since cefuroxime is primarily eliminated by the kidney, the presence of hepatic dysfunction is expected to have no effect on the pharmacokinetics of cefuroxime.

Pharmacokinetic/pharmacodynamic 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 (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T>MIC).

Absorption

After intramuscular (IM) injection of cefuroxime to normal volunteers, the mean peak serum concentrations ranged from 27 to 35 µg/mL for a 750 mg dose and from 33 to 40 µg/mL for a 1000 mg dose, and were achieved within 30 to 60 minutes after administration. Following intravenous (IV) doses of 750 and 1500 mg, serum concentrations were approximately 50 and 100 µg/mL, respectively, at 15 minutes.

AUC and C_max appear to increase linearly with increase in dose over the single dose range of 250 to 1000 mg following IM and IV administration. There was no evidence of accumulation of cefuroxime in the serum from normal volunteers following repeat intravenous administration of 1500 mg doses every 8 hours.

Distribution

Protein binding has been stated as 33 to 50%, depending on the methodology used. The average volume of distribution ranges from 9.3 to 15.8 L/1.73 m² following IM or IV administration over the dosage range of 250 to 1000 mg. Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum and aqueous humour. Cefuroxime passes the blood-brain barrier when the meninges are inflamed.

Biotransformation

Cefuroxime is not metabolised.

Elimination

Cefuroxime is excreted by glomerular filtration and tubular secretion. The serum half-life after either intramuscular or intravenous administration is approximately 70 minutes. There is an almost complete recovery (85 to 90%) of unchanged cefuroxime in urine within 24 hours of administration. The majority of the cefuroxime is excreted within the first 6 hours. The average renal clearance ranges from 114 to 170 mL/min/1.73 m² following IM or IV administration over the dosage range of 250 to 1000 mg.

Special patient populations

Gender

No differences in the pharmacokinetics of cefuroxime were observed between males and females following a single IV bolus injection of 1000 mg of cefuroxime as the sodium salt.

Elderly

Following IM or IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function.

Paediatrics

The serum half-life of cefuroxime has been shown to be substantially prolonged in neonates according to gestational age. However, in older infants (aged >3 weeks) and in children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.

Renal impairment

Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. C1cr <20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by haemodialysis and peritoneal dialysis.

Hepatic impairment

Since cefuroxime is primarily eliminated by the kidney, hepatic dysfunction is not expected to have an effect on the pharmacokinetics of cefuroxime.

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 (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T>MIC).

The systemic exposure following intracameral injection has not been studied but is expected to be negligible.

After intracameral injection at the recommended single dose of 0.1ml of a 10mg/ml solution of Orextil in cataract patients, the mean intracameral level of Orextil was 2614 ± 209mg/l (10 patients) 30 seconds and 1027 ± 43mg/l (9 patients) 60 minutes after drug administration.

Absorption

After intramuscular (IM) injection of cefuroxime to normal volunteers, the mean peak serum concentrations ranged from 27 to 35 µg/mL for a 750 mg dose and from 33 to 40 µg/mL for a 1000 mg dose, and were achieved within 30 to 60 minutes after administration. Following intravenous (IV) doses of 750 and 1500 mg, serum concentrations were approximately 50 and 100 µg/mL, respectively, at 15 minutes.

AUC and C_max appear to increase linearly with increase in dose over the single dose range of 250 to 1000 mg following IM and IV administration. There was no evidence of accumulation of cefuroxime in the serum from normal volunteers following repeat intravenous administration of 1500 mg doses every 8 hours.

Distribution

Protein binding has been stated as 33 to 50%, depending on the methodology used. The average volume of distribution ranges from 9.3 to 15.8 L/1.73 m² following IM or IV administration over the dosage range of 250 to 1000 mg. Concentrations of cefuroxime in excess of the minimum inhibitory levels for common pathogens can be achieved in the tonsilla, sinus tissues, bronchial mucosa, bone, pleural fluid, joint fluid, synovial fluid, interstitial fluid, bile, sputum and aqueous humour. Cefuroxime passes the blood-brain barrier when the meninges are inflamed.

Biotransformation

Cefuroxime is not metabolised.

Elimination

Cefuroxime is excreted by glomerular filtration and tubular secretion. The serum half-life after either intramuscular or intravenous injection is approximately 70 minutes. There is an almost complete recovery (85 to 90%) of unchanged cefuroxime in urine within 24 hours of administration. The majority of the cefuroxime is excreted within the first 6 hours. The average renal clearance ranges from 114 to 170 mL/min/1.73 m² following IM or IV administration over the dosage range of 250 to 1000 mg.

Special patient populations

Gender

No differences in the pharmacokinetics of cefuroxime were observed between males and females following a single IV bolus injection of 1000 mg of cefuroxime as the sodium salt.

Elderly

Following IM or IV administration, the absorption, distribution and excretion of cefuroxime in elderly patients are similar to younger patients with equivalent renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in cefuroxime dose selection, and it may be useful to monitor renal function.

Paediatrics

The serum half-life of cefuroxime has been shown to be substantially prolonged in neonates according to gestational age. However, in older infants (aged >3 weeks) and in children, the serum half-life of 60 to 90 minutes is similar to that observed in adults.

Renal impairment

Cefuroxime is primarily excreted by the kidneys. As with all such antibiotics, in patients with markedly impaired renal function (i.e. C1_cr <20 mL/minute) it is recommended that the dosage of cefuroxime should be reduced to compensate for its slower excretion. Cefuroxime is effectively removed by haemodialysis and peritoneal dialysis.

Hepatic impairment

Since cefuroxime is primarily eliminated by the kidney, hepatic dysfunction is not expected to have an effect on the pharmacokinetics of cefuroxime.

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 (%T) that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefuroxime for individual target species (i.e. %T>MIC).

None.

Cefuroxime is compatible with most commonly used intravenous fluids and electrolyte solutions.

The pH of 2.74% w/v sodium bicarbonate injection BP considerably affects the colour of solutions and therefore this solution is not recommended for the dilution of Cefuroxime. However, if required, for patients receiving sodium bicarbonate injection by infusion the Cefuroxime solution may be introduced into the tube of the giving set.

Cefuroxime should not be mixed in the syringe with aminoglycoside antibiotics.

Cefuroxime is compatible with most commonly used intravenous fluids and electrolyte solutions.

The pH of 2.74% w/v sodium bicarbonate injection BP considerably affects the colour of solutions and therefore this solution is not recommended for the dilution of Orextil. However, if required, for patients receiving sodium bicarbonate injection by infusion the Orextil may be introduced into the tube of the giving set.

Orextil should not be mixed in the syringe with aminoglycoside antibiotics.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Constitution/Administration instructions

The bottle should be shaken vigorously before the medication is taken.

The reconstituted suspension when refrigerated between 2 and 8°C can be kept for up to 10 days.

If desired, Orextil suspension from multidose bottles can be further diluted in cold fruit juices, or milk drinks and should be taken immediately.

Directions for reconstituting suspension in multidose bottles

1. Shake the bottle to loosen the content. All the granules should be free-flowing in the bottle. Remove the cap and the heat-seal membrane. If the latter is damaged or not present, the product should be returned to the pharmacist.

2. Add the total amount of cold water as stated on the label or up to the volume line on the cup provided (if supplied). If the water was previously boiled it must be allowed to cool to room temperature before adding. Do not mix Orextil granules for oral suspension with hot or warm liquids. Cold water must be used to prevent the suspension becoming too thick.

3. Replace the cap. Allow the bottle to stand to allow the water to fully soak through the granules; this should take about one minute.

4. Invert the bottle and shake well (for at least 15 seconds) until all the granules have mixed with the water.

5. Turn the bottle into an upright position and shake well for one minute until all the granules have blended with the water.

Store the Orextil suspension immediately at between 2 and 8°C (do not freeze) and let it rest for at least one hour before taking the first dose. The reconstituted suspension when refrigerated between 2 and 8°C can be kept for up to 10 days.

Always shake the bottle well before taking the medication.

Directions for reconstituting suspension from sachets: -

1. Empty granules from sachet into a glass.

2. Add a small volume of cold water.

3. Stir well and drink immediately.

The reconstituted suspension or granules should not be mixed with hot liquids.

Intramuscular injection: Add 6ml of water for injections to 1.5 g. Shake gently to produce a suspension.

Intravenous administration: Dissolve cefuroxime in water for injections using at least 15ml for 1.5g. For short intravenous infusion, 1.5g may be dissolved in 50ml of water for injections. Reconstituted solutions may be diluted with:

5% or 10% dextrose

5% dextrose containing 0.2%, 0.225%, 0.45% or 0.9% sodium chloride injection

5% dextrose containing 20mEq potassium chloride

0.9% sodium chloride injection

M/6 sodium lactate injection

Ringer's injection

Lactated Ringer's injection

Heparin (10 and 50 units/ml) in 0.9% sodium chloride injection

10 and 40 mEqL potassium chloride in 0.9% sodium chloride injection

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

APROKAM must be administered by intracameral injection, by an ophthalmic surgeon in the recommended aseptic conditions of cataract surgery.

VIAL IS FOR SINGLE USE ONLY.

USE ONE VIAL FOR ONE PATIENT. Stick the flag label of the vial on the patient's file.

To prepare the product for intracameral administration, please adhere to the following instructions:

1. Withdraw flip-off cap

2. Before inserting a sterile needle, the outer part of the rubber stopper of the vial should be disinfected.

3. Push the needle vertically into the centre of the vial stopper, keeping the vial in an upright position. Then, inject into the vial 5ml of sodium chloride 9mg/ml (0.9%) solution for injection using aseptic technique.

4. Shake gently until the solution is free from visible particles.

5. Assemble a sterile needle (18G x 1½”, 1.2mm x 40mm) with 5-micron filter (acrylic copolymer membrane on a non-woven nylon) onto a 1ml sterile syringe. Push this syringe vertically into the centre of the vial stopper, keeping the vial in an upright position.

6. Aseptically aspire at least 0.1ml of the solution.

7. Disconnect the 5-micron filter needle from the syringe and assemble the syringe with an appropriate anterior chamber cannula.

8. Carefully expel the air from the syringe and adjust the dose to the 0.1ml mark on the syringe. The syringe is ready for injection.

The reconstituted solution should be visually inspected and should only be used if it is a colourless to yellowish solution free from visible particles. It has a pH and osmolality close to the physiological values (pH about 7.3 and osmolality about 335mosmol/kg).

After use, discard the remaining of the reconstituted solution. Do not keep it for subsequent use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Instructions for constitution

Table 4. Additional volumes and concentrations which may be useful when fractional doses are required.

* Reconstituted solution to be added to 50 or 100 mL of compatible infusion fluid (see information on compatibility, below)

** The resulting volume of the solution of cefuroxime in reconstitution medium is increased due the displacement factor of the drug substance resulting in the listed concentrations in mg/mL.

Orextil 750 mg and 1.5 g powder for solution for infusion (Monovial presentation)

Preparation of solution for intravenous infusion

The contents of the Monovial are added to small volume infusion bags containing 0.9% w/v Sodium Chloride Injection BP, or 5% Dextrose Injection, or another compatible fluid.

1. Peel off the removable top part of the label and remove the cap.

2. Insert the needle of the Monovial into the additive port of the infusion bag.

3. To activate, push the plastic needle holder of the Monovial down onto the vial shoulder until a "click" is heard.

4. Holding it upright, fill the vial to approximately two-thirds capacity by squeezing the bag several times.

5. Shake the vial to reconstitute the cefuroxime sodium.

6. With the vial uppermost, transfer the reconstituted cefuroxime sodium into the infusion bag by squeezing and releasing the bag.

7. Repeat steps 4 to 6 to rinse the inside of the vial. Dispose of the empty Monovial safely. Check that the powder has dissolved, and that the bag has no leaks.

Compatibility

1.5 g cefuroxime sodium constituted with 15 mL Water for Injection may be added to metronidazole injection (500 mg/100 mL) and both retain their activity for up to 24 hours below 25°C.

1.5 g cefuroxime sodium is compatible with azlocillin 1 g (in 15 mL) or 5 g (in 50 mL) for up to 24 hours at 4°C or 6 hours below 25°C.

Cefuroxime sodium (5 mg/mL) in 5% w/v or 10% w/v xylitol injection may be stored for up to 24 hours at 25°C.

Cefuroxime sodium is compatible with aqueous solutions containing up to 1% lidocaine hydrochloride.

Cefuroxime sodium is compatible with the following infusion fluids. It will retain potency for up to 24 hours at room temperature in:

0.9% w/v Sodium Chloride Injection BP

5% Dextrose Injection BP

0.18% w/v Sodium Chloride plus 4% Dextrose Injection BP

5% Dextrose and 0.9% w/v Sodium Chloride Injection BP

5% Dextrose and 0.45% Sodium Chloride Injection

5% Dextrose and 0.225% Sodium Chloride Injection

10% Dextrose Injection

10% Invert Sugar in Water for Injection

Ringer's Injection USP

Lactated Ringer's Injection USP

M/6 Sodium Lactate Injection

Compound Sodium Lactate Injection BP (Hartmann's Solution).

The stability of cefuroxime sodium in 0.9% w/v Sodium Chloride Injection BP and in 5% Dextrose Injection is not affected by the presence of hydrocortisone sodium phosphate.

Cefuroxime sodium has also been found compatible for 24 hours at room temperature when admixed in IV infusion with:

Heparin (10 and 50 units/mL) in 0.9% w/v Sodium Chloride Injection BP; Potassium Chloride (10 and 40 mEqL) in 0.9% w/v Sodium Chloride Injection BP.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.