Zinoximor is indicated for the treatment of the infections listed below in adults and children

from the age of 3 months (see sections 4.4 and 5.1).

• 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

Posology

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

Table 1. Adults and children ( ≥ 40 kg)

Indication	Dosage
Acute tonsillitis and pharyngitis, acute bacterial sinusitis	250 mg twice daily
Acute otitis media	500 mg twice daily
Acute exacerbations of chronic bronchitis	500 mg twice daily
Cystitis	250 mg twice daily
Pyelonephritis	250 mg twice daily
Uncomplicated skin and soft tissue infections	250 mg twice daily
Lyme disease	500 mg twice daily for 14 days (range of 10 to 21 days)

Table 2. Children (<40 kg)

Indication	Dosage
Acute tonsillitis and pharyngitis, acute bacterial sinusitis	10 mg/kg twice daily to a maximum of 125 mg twice daily
Children aged two years or older with otitis media or, where appropriate, with more severe infections	15 mg/kg twice daily to a maximum of 250 mg twice daily
Cystitis	15 mg/kg twice daily to a maximum of 250 mg twice daily
Pyelonephritis	15 mg/kg twice daily to a maximum of 250 mg twice daily for 10 to 14 days
Uncomplicated skin and soft tissue infections	15 mg/kg twice daily to a maximum of 250 mg twice daily
Lyme disease	15 mg/kg twice daily to a maximum of 250 mg twice daily for 14 days (10 to 21 days)

There is no experience of using Zinoximor 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 (see section 5.2).

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 Zinoximor in renal impairment

Creatinine clearance	T1/2 (hrs)	Recommended dosage
≥30 mL/min/1.73 m2	1.4–2.4	no dose adjustment necessary (standard dose of 125 mg to 500 mg given twice daily)
10-29 mL/min/1.73 m2	4.6	standard individual dose given every 24 hours
<10 mL/min/1.73 m2	16.8	standard individual dose given every 48 hours
Patients on haemodialysis	2–4	a further standard individual dose should be given at the end of each 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.

Method of administration

Oral use

Zinoximor tablets should be taken after food for optimum absorption.

Zinoximor tablets should not be crushed and are therefore unsuitable for treatment of patients who cannot swallow tablets. In children Zinoximor oral suspension may be used.

Hypersensitivity to cefuroxime or to any of the excipients listed in section 6.1. 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 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 betalactam agent. Caution should be used if cefuroxime is given to patients with a history of nonsevere 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 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 (see section 4.8). 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 Zinoximor tablets contain parabens which may cause allergic reactions (possibly delayed).

Drugs which reduce gastric acidity may result in a lower bioavailability of cefuroxime axetil

compared with that of the fasting state and tend to cancel the effect of enhanced absorption

after food.

Cefuroxime axetil may affect the gut flora, leading to lower oestrogen reabsorption and

reduced efficacy of combined oral contraceptives.

Cefuroxime is excreted by glomerular filtration and tubular secretion. Concomitant use of

probenicid is not recommended. Concurrent administration of probenecid significantly

increases the peak concentration, area under the serum concentration time curve and

elimination half-life of cefuroxime.

Concomitant use with oral anticoagulants may give rise to increased INR.

Teratogenic Effects

Pregnancy Category B. Reproduction studies have been performed in mice at doses up to

3,200 mg/kg/day (14 times the recommended maximum human dose based on mg/m2) and in

rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based

on mg/m2) and have revealed no evidence of impaired fertility or harm to the fetus due to

cefuroxime axetil. There are, however, no adequate and well-controlled studies in pregnant

women. Because animal reproduction studies are not always predictive of human response,

this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Cefuroxime axetil has not been studied for use during labor and delivery.

Nursing Mothers

Because cefuroxime is excreted in human milk, consideration should be given to discontinuing

nursing temporarily during treatment with cefuroxime axetil.

Fertility

There are no data on the effects of cefuroxime axetil on fertility in humans. Reproductive

studies in animals have shown no effects on fertility.

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.

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). System organ class Common Uncommon Not known Infections and infestations Candida overgrowth   Clostridium difficileovergrowth Blood and lymphatic system disorders eosinophilia positive Coomb's test,thrombocytopenia, leukopenia (sometimes profound) haemolytic anaemia Immune system disorders     drug fever, serum sickness, anaphylaxis, Jarisch-Herxheimer reaction Nervous system disorders headache, dizziness     Gastrointestinal disorders diarrhoea, nausea, abdominal pain vomiting pseudomembranous colitis Hepatobiliary disorders transient increases of hepatic enzyme levels   jaundice (predominantly cholestatic), hepatitis Skin and subcutaneous tissue disorders   skin rashes urticaria, pruritus, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (exanthematic necrolysis) (see Immune system disorders), angioneurotic oedema Description of selected adverse reactions Cephalosporins as a class tend to be absorbed onto the surface of red cells membranes and react with antibodies directed against the drug to produce a positive Coombs' test (which can interfere with cross-matching of blood) and very rarely haemolytic anaemia. Transient rises in serum liver enzymes have been observed which are usually reversible. Paediatric population The safety profile for cefuroxime axetil in children is consistent with the profile in adults.   To report any side effect(s) • Saudi Arabia: National Pharmacovigilance and Drug Safety Center (NPC) Fax: +966-11-205-7662 Call NPC at +966-11-2038222 Exts: 2317-2356-2353-2354-2334-2340 Toll free phone: 8002490000 E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc • Other GCC States: Please contact the relevant competent authority.

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 (see sections 4.2 and 4.4).

Serum levels of cefuroxime can be reduced by haemodialysis and 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 betalactamases

(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:

 

Microorganism	Breakpoints (mg/L)
	S	R
Enterobacteriaceae 1, 2	≤8	>8
Staphylococcus spp.	Note3	Note3
Streptococcus A, B, C and G	Note4	Note4
Streptococcus pneumoniae	≤0.25	>0.5
Moraxella catarrhalis	≤0.125	>4
Haemophilus influenzae	≤0.125	>1
Non-species related breakpoints1	IE5	IE5
1 The cephalosporin breakpoints for Enterobacteriaceae will detect all clinically important resistance mechanisms (including ESBL and plasmid mediated AmpC). Some strains that produce beta-lactamases are susceptible or intermediate to 3rd or 4th generation cephalosporins with these breakpoints and should be reported as found, i.e. the presence or absence of an ESBL does not in itself influence the categorization of susceptibility. In many areas, ESBL detection and characterization is recommended or mandatory for infection control purposes. 2 Uncomplicated UTI (cystitis) only (see section 4.1). 3 Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility except for ceftazidme and cefixime and ceftibuten, which do not have breakpoints and should not be used for staphylococcal infections. 4 The beta-lactam susceptability of beta-haemolytic streptococci groups A, B, C and G is inferred from the penicillin susceptibility. 5 insufficient evidence that the species in question is a good target for therapy with the drug. An MIC with a comment but without an accompanying S or R-categorization may be reported.

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.

Commonly susceptible species

Gram-positive aerobes: Staphylococcus aureus (methicillin susceptible)* Streptococcus pyogenes Streptococcus agalactiae

Gram-negative aerobes: Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis

Spirochaetes: Borrelia burgdorferi

Microorganisms for which acquired resistance may be a problem

Gram-positive aerobes: Streptococcus pneumoniae

Gram-negative aerobes: Citrobacter freundii Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Proteus mirabilis Proteus spp. (other than P. vulgaris) Providencia spp.

Gram-positive anaerobes: Peptostreptococcus spp. Propionibacterium spp.

Gram-negative anaerobes: Fusobacterium spp. Bacteroides spp.

Inherently resistant microorganisms

Gram-positive aerobes: Enterococcus faecalis Enterococcus faecium

Gram-negative aerobes: Acinetobacter spp. Campylobacter spp. Morganella morganii Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens

Gram-negative anaerobes: Bacteroides fragilis

Others: Chlamydia spp. Mycoplasma spp. Legionella spp.

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

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 (2.9 μg/mL for a 125

mg dose, 4.4 μg/mL for a 250 mg dose, 7.7 μg/mL for a 500 mg dose and 13.6 μg/mL for a

1000 mg dose) occur approximately 2.4 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

(see section 4.2).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 (see section 4.2).

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 (see

section 4.2). 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.

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).

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.

Microcrystalline Cellulose

Sodium Lauryl Sulphate

Croscarmellose Sodium

Colloidal Silicone Dioxide

Lubritab

Methocel E15

Propylene Glycol

Polyethylene Glycol 4000

Titanium Dioxide

Talc

Not applicable

36 months

Store below 30 °C.

Two Aluminum- Aluminum blisters of 7 tablets each, packed in a printed carton with folded leaflet.

No special requirements.