Aksosef

Aksosef 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.

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.

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 Aksosef 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 Aksosef 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.

Intracameral use. One vial for single-use only.

Posology

Adults:

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

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 Aksosef 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.

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).

Hypersensitivity to Aksosef or to the cephalosporin group of antibiotics.

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.

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 Aksosef 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 Aksosef; nevertheless, this risk cannot be excluded and in the post-surgical surveillance, physicians should have in mind this potential risk.

No studies on the effects on the ability to drive and use machines have been performed. However, as this medicine may cause dizziness, patients should be warned to be cautious when driving or operating machinery.

Not relevant.

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.

No particular adverse effects were reported in the literature when Aksosef 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

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.

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

Inadvertent high-dose (3-fold the recommended dose) intracameral Aksosef was administered to 6 patients following an incorrect dilution due to homemade Aksosef 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 Aksosef 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 Aksosef (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.

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.

ATC classification

Pharmacotherapeutic group: Sensory Organs - Ophthalmologicals - Antiinfectives - Antibiotics

ATC code: S01AA27

Mechanism of action

Aksosef 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 Aksosef for individual target species (i.e. %T>MIC).

After intracameral injection of 1 mg Aksosef, Aksosef 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 Aksosef may be due to one or more of the following mechanisms:

- hydrolysis by beta-lactamases. Aksosef 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 Aksosef;

- outer membrane impermeability, which restricts access of Aksosef 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 Aksosef.

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

Beta-lactamase negative, ampicillin resistant (BLNAR) strains of H. influenzae should be considered resistant to Aksosef 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 Aksosef 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 Aksosef” groups and 5 in “intracameral Aksosef” groups) presented with endophthalmitis, of whom 20 (17 in “without Aksosef” groups and 3 in “intracameral Aksosef” groups) were classified as having proven infective endophthalmitis. Among these 20 proven endophthalmitis: 10 patients are in group “placebo eye drops and without Aksosef”, 7 patients in group “levofloxacine eye drops and without Aksosef”, 2 patients in group “placebo eye drops and intracameral Aksosef” and 1 patient in group “levofloxacine eye drops and intracameral Aksosef. The administration of intracameral Aksosef 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 Aksosef in postoperative endophthalmitis.

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).

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 Aksosef in cataract patients, the mean intracameral level of Aksosef was 2614 ± 209mg/l (10 patients) 30 seconds and 1027 ± 43mg/l (9 patients) 60 minutes after drug administration.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development. No carcinogenicity studies have been performed; however, there is no evidence to suggest carcinogenic potential.

Gamma glutamyl transpeptidase activity in rat urine is inhibited by various cephalosporins, however the level of inhibition is less with cefuroxime. This may have significance in the interference in clinical laboratory tests in humans.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Intravitreal injection of 1 mg Aksosef in albino rabbits resulted in levels of 19-35mg/l and 600-780mg/l after 30min following injection in the aqueous and in the vitreous, respectively. Levels after 6 h decreased to 1.9-7.3 and 190- 260mg/l respectively in these two structures. There was no increase in the intraocular pressure during the first 3 days. Histopathology showed no degenerative changes compared to saline.

ERG: a-, b- and c- waves diminished up until 14 days both in the control and antibiotic-injected eyes.

Recovery occurred and may be slower than in control. ERG showed no definite changes suggestive of retinal toxicity up to 55 days after intravitreal administration.

None.

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, Aksosef 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 Aksosef 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 Aksosef 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.

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.