Product Index

Not to be sold by retail without prescription of a Registered Medical Practitioner

Qualitative And Quantitative Composition

Each film-coated tablet contains:

Cefuroxime Axetil, IP

equivalent to Cefuroxime …. 500 mg

Colour: Titanium dioxide

Dosage Form and Strength

Oral Cefuroxime Axetil Tablets 500 mg.

Clinical Particulars

Therapeutic Indications

Cefuroxime tablets are indicated for lower & upper respiratory tract infection, UTI, gynaecological infection, skin or soft tissue infection etc.

Posology and Method of Administration

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

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)

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.

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

Cefuroxime axetil tablets should be taken after food for optimum absorption.

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

Contraindications

Cefuroxime products are contraindicated in patients with a known allergy to the cephalosporin group of antibiotics.

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

Special Warnings and Precautions for Use

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.

Severe cutaneous adverse reactions (SCAR), such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in patients receiving cefuroxime.

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.

If signs and symptoms suggestive of these reactions appear, cefuroxime should be withdrawn immediately and an alternative treatment should be considered (as appropriate).

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.

Drug Interactions

Drugs that reduce gastric acidity may result in a lower bioavailability of cefuroxime compared with that of the fasting state and tend to cancel the effect of postprandial absorption.

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

Use in Special Populations

Pregnant women

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. Cefuroxime axetil should be prescribed to pregnant women only if the benefit outweighs the risk.

Lactating women 

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.

Paediatric Patients 

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

Patients with Hepatic Impairment

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

Patients with Renal Impairment

Reducing the dosage of cefuroxime is recommended for adult patients with severe renal impairment (creatinine clearance <30 mL/min) (refer to DOSAGE AND ADMINISTRATION).

Geriatric Use

Of the total number of subjects who received cefuroxime axetil in 20 clinical studies of cefuroxime, 375 were aged 65 years and over while 151 were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. The geriatric patients reported somewhat fewer gastrointestinal events and less frequent vaginal candidiasis compared with patients aged 12 to 64 years; however, no clinically significant differences were reported between the elderly and younger adult patients. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

Drug/Laboratory Test Interactions

A false-positive reaction for glucose in the urine may occur with copper reduction tests (Benedict's or Fehling's solution), but not with enzyme-based tests for glycosuria. As a false-negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase method be used to determine blood/plasma glucose levels in patients receiving cefuroxime axetil. The presence of cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method.

Effects on Ability to Drive and Use Machines

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.

Undesirable Effects

The most common adverse reactions are Candida overgrowth, eosinophilia, headache, dizziness, gastro intestinal 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 difficile overgrowth
Blood and lymphatic system disorders	eosinophilia	positive Coombs' 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, severe cutaneous adverse reactions (SCARs), including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (exanthematic necrolysis) (TEN) , drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP), angioneurotic oedema, Fixed Drug Eruption (FDE).
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.

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdosage

Overdosage of cephalosporins can cause cerebral irritation, leading to convulsions. Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.

Pharmacological Properties

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:

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. 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 susceptibility 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)* Coagulase negative staphylococcus (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.

Pharmacokinetic Properties

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 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.

Paediatric population

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.

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 Properties

Animal Toxicology or Pharmacology

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.

Description

The chemical name of cefuroxime axetil (1-(acetyloxy) ethyl ester of cefuroxime) is (RS)-1­hydroxyethyl (6R,7R)-7--3-(hydroxymethyl)-8-oxo-5-thia-1­azabicyclo-oct-2-ene-2-carboxylate, 7²-(Z)-(O-methyl-oxime), 1-acetate 3-carbamate. Its molecular formula is C20H22N4O10S, and it has a molecular weight of 510.48.

Cefuroxime axetil is in the amorphous form and has the following structural formula:

Pharmaceutical Particulars

Incompatibilities

NA

Shelf-Life

Please see on the strip

Packaging Information

NOVACEF 500 Tablets ………….. Strip pack of 10 tablets

Storage and Handling Instructions

Store protect from light and moisture at a temperature not exceeding 30^oC. Keep out of the reach of children.

Patient Counselling Information

1. What is NOVACEF and what is it used for?

Cefuroxime tablets are indicated for lower & upper respiratory tract infection, UTI, gynaecological infection, skin or soft tissue infection etc.

2. What do you need to know before you take NOVACEF?

Do not take Cefuroxime:

• if you are allergic to to the cephalosporin group of antibiotics.
• if you have history of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of betalactam antibacterial agent (penicillins, monobactams and carbapenems).

Warnings and precautions

Talk with your doctor or pharmacist before taking Cefuroxime if you have:

• Hypersensitivity reactions
• Overgrowth of non-susceptible microorganisms
• The development of a positive Coombs' Test associated with the use of cefuroxime may interfere with cross matching of blood.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any of the following medicines:

Drugs that reduce gastric acidity may result in a lower bioavailability of cefuroxime compared with that of the fasting state and tend to cancel the effect of postprandial absorption.

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

Cefuroxime with food and drink

Cefuroxime axetil tablets should be taken after food for optimum absorption.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

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.

3. What are the possible side effects of NOVACEF?

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you have any of the following symptoms of a severe allergic reaction stop taking this medicine and tell your doctor immediately or go to the casualty department at your nearest hospital

• Sudden difficulty in breathing, speaking and swallowing
• Swelling of the lips, tongue, face and neck
• Extreme dizziness or collapse
• Severe or itchy skin rash, especially if this shows blistering and there is soreness of the eyes, mouth or genital organs.
• Fixed Drug Eruption (FDE)

If you experience any of the following side effects contact your doctor as soon as possible

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

Reporting of side effects:

For Adverse Events / Complaints: call on Cipla Toll free number (for India)18002677779 or email to drugsafety@cipla.com

How to store this medicine?

Store protect from light and moisture at a temperature not exceeding 30^oC.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after Expiry.

The expiry date refers to the last day of that month.

The medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Details of the Manufacturers

Mfd. By: Cipla Ltd.

L-1/1, L-1/2/2, L-2, Additional MIDC,

SATARA-415004

Details of Permission or Licence Number With Date

M.L. PD/475A dated 11/02/2020

Date of Revision

16/02/2023