Cefuroxime (as cefuroxime axetil) ...... 500 mg
Excipients q.s ……………… 1 tablet
Film coated tablet.
Product description
A cylindrical, white to off-white, film-coated tablet, plain on both sides, undamaged edges.
Box of 2 blisters x 5 film coated tablets.
Pharmacotherapeutic group: 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.
Commonly susceptible species
Gram-positive aerobes: Staphylococcus aureus (methicillin susceptible)*, Coagulase negative staphylococcus (methicillin susceptible), Streptococcus pyogenes, Streptococcus agalactiae
Gram-negative aerobes: Haemophilus influenza, 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 pneumonia, 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 peak serum levels (2.9 mcg/ml for a 125 mg dose, 4.4 mcg/ml for a 250 mg dose, 7.7 mcg/ml for a 500 mg dose and 13.6 mcg/ml for a 1000 mg dose) occur approximately 2.4 hours after dosing when taken with food. 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).
Preclinical safety data
Animal toxicity studies have shown that cefuroxime axetil has low toxicity and no significant findings.
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.
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 Coombs 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.
Pregnancy
There are limited data from the use of cefuroxime in pregnant women. Studies in animals have shown no harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Haginat should be prescribed to pregnant women only if the benefit outweighs the risk.
Breastfeeding
Cefuroxime is excreted in human milk in small quantities. Adverse effects at therapeutic doses are not expected, although a risk of diarrhoea and fungus infection of the mucous membranes cannot be excluded. Breastfeeding might have to be discontinued due to these effects. The possibility of sensitisation should be taken into account. Cefuroxime should only be used during breastfeeding after benefit/risk assessment by the physician in charge.
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.
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.
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 are listed below by 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).
Infections and infestations
Common: Candida overgrowth
Not known: Clostridium difficile overgrowth
Blood and lymphatic system disorders
Common: eosinophilia
Uncommon: positive Coomb's test, thrombocytopenia, leukopenia (sometimes profound)
Not known: haemolytic anaemia
Immune system disorders
Not known: drug fever, serum sickness, anaphylaxis, Jarisch-Herxheimer reaction
Nervous system disorders
Common: headache, dizziness
Gastrointestinal disorders
Common: diarrhoea, nausea, abdominal pain
Uncommon: vomiting
Not known: pseudomembranous colitis
Hepatobiliary disorders
Common: transient increases of hepatic enzyme levels
Not known: jaundice (predominantly cholestatic), hepatitis
Skin and subcutaneous tissue disorders
Uncommon: skin rashes
Not known: 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.
Please inform your doctor of all undesirable effects upon drug administration.
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.
Store in dry places, not exceeding 30oC, protect from light.
Haginat is an oral prodrug of the bactericidal cephalosporin antibiotic cefuroxime, which is resistant to most beta-lactamases and is active against a wide range of Gram-positive and Gram-negative organisms.
It is indicated for the treatment of infections caused by susceptible bacteria.
Susceptibility to Haginat will vary with geography and time and local susceptibility data should be consulted where available (see section Pharmacodynamic properties).
Indications include:
Upper respiratory tract infections for example, ear, nose and throat infections, such as otitis media, sinusitis, tonsillitis and pharyngitis.
Lower respiratory tract infections for example, pneumonia, acute bronchitis, and acute exacerbations of chronic bronchitis.
Genito-urinary tract infections for example, pyelonephritis, cystitis and urethritis.
Skin and soft tissue infections for example, furunculosis, pyoderma and impetigo.
Gonorrhoea, acute uncomplicated gonococcal urethritis, and cervicitis.
Treatment of early Lyme disease and subsequent prevention of late Lyme disease in adults and children from 12 years old and above.
Cefuroxime is also available as the sodium salt for parenteral administration. This permits the use of sequential therapy with the same antibiotic, when a change from parenteral to oral therapy is clinically indicated.
Where appropriate cefuroxime is effective when used following initial parenteral cefuroxime sodium in the treatment of pneumonia and acute exacerbations of chronic bronchitis.
Hypersensitivity to cefuroxime or to any of the excipients listed in the product.
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).
METHOD OF ADMINISTRATION
Oral use.
Cefuroxime axetil tablets should be taken after food for optimum absorption.
Haginat film-coated tablets should not be crushed and are therefore unsuitable for treatment of patients, such as younger children, who cannot swallow tablets. In children, Haginat 125 oral suspension may be used.
POSOLOGY
The usual course of therapy is seven days (may range from five to ten days).
Adults
Most infections: 250 mg twice daily.
Urinary tract infections: 125 mg twice daily.
Mild to moderate lower respiratory tract infections e.g. bronchitis: 250 mg twice daily.
More severe lower respiratory tract infections, or if pneumonia is suspected: 500 mg twice daily.
Pyelonephritis: 250 mg twice daily.
Uncomplicated gonorrhoea: single dose of 1 g.
Lyme disease in adults and children over the age of 12 years: 500 mg twice daily for 20 days.
Sequential therapy
Pneumonia:
1.5 g cefuroxime sodium three times a day or twice a day (intravenous (i.v.) or intramuscular (i.m)) for 48 to 72 hours, followed by cefuroxime axetil oral therapy 500 mg twice a day for 7 to10 days.
Acute exacerbations of chronic bronchitis:
750 mg cefuroxime sodium three times a day or twice a day (i.v. or i.m.) for 48 to 72 hours, followed by cefuroxime axetil oral therapy 500 mg twice a day for 5 to 10 days. Duration of both parenteral and oral therapy is determined by the severity of the infection and the clinical status of the patient.
Children aged from 3 months to 12 years
Most infections: 125 mg twice daily, to a maximum of 250 mg daily.
Children aged two years or older with otitis media or, where appropriate, with more severe infections: 250 mg twice daily, to a maximum of 500 mg daily.
Pyelonephritis: 250 mg twice daily for 10 - 15 days for 10 - 14 days.
Children < 6 years old: Haginat oral suspension may be used.
There is no experience of using Haginat in children under the age of 3 months.
Note:
With a dosage of 500 mg: Haginat 500 should be used.
With a dosage of 250 mg: Haginat 250 should be used.
With a dosage of 125 mg: Haginat 125 should be used.
Renal impairment
Cefuroxime is primarily excreted by the kidneys. In patients with markedly impaired renal function it is recommended that the dosage of cefuroxime be reduced to compensate for its slower excretion (see the table below)
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