1. NAME OF THE MEDICINAL PRODUCT

Cefixime 400 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 447.63 mg cefixime trihydrate, equivalent to 400 mg cefixime anhydrous

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

White to off white, film-coated, rectangular shaped tablet having partial break line on both sides.

4.1    Therapeutic indications

Cefixime is an orally active cephalosporin antibiotic indicated for the treatment of the following infections when caused by susceptible organisms (see section 5.1):

Acute exacerbations of chronic bronchitis Community-acquired Pneumonia Uncomplicated lower urinary tract infections Uncomplicated pyelonephritis

In the treatment of:

Otitis media

Sinusitis

Pharyngitis

The use of cefixime should be reserved for infections in which the causative organism is known or suspected to be resistant to other commonly used antibacterial agents or when treatment failure may carry significant risk.

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

4.2    Posology and method of administration

Posology

Adults

The recommended dose for adults is 400 mg daily taken as a single dose or 2 x 200mg daily dose (see section 4.4 and 5.1).

The usual course of treatment is 7 days. This may be continued for up to 14 days if required.

Elderly patients

Elderly patients may be given the same dose as recommended for adults. Renal function should be assessed and dosage should be adjusted in severe renal impairment (see above and section 4.4).

Adolescents > 12 years of age

Adolescents > 12 years_of age may be given the same dose as recommended for adults.

Paediatric population

Children from 6 months to 11 years of age

It is recommended that Children from 6 months to 11 years of age be given cefixime as an oral suspension. The recommended dosage for children is 8 mg / kg body weight / day administered as a single dose or in two divided doses.

Children less than 6 months of age

The safety and efficacy of cefixime has not been established in children less than 6 months of age.

Renal insufficiency

Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be given in patients with creatinine clearances of 20 ml/min or greater. In patients whose creatinine clearance is less than 20 ml/min, it is recommended that a dose of 200 mg once daily should not be exceeded. The dose and regimen for patients who are maintained on chronic ambulatory peritoneal dialysis or haemodialysis should follow the same recommendation as that for patients with creatinine clearances of less than 20 ml/min.

There are insufficient data regarding use of cefixime in the paediatric and adolescent age group in the presence of renal insufficiency. Therefore, the use of cefixime in these patient-groups is not recommended.

Method of administration

For oral use. Cefixime tablets should be taken with a sufficient amount of water. Cefixime may be taken with or without food (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance cefixime, other cephalosporin antibiotics or to any of the excipients listed in section 6.1.

Previous, immediate and/or severe hypersensitivity reaction to penicillin or any beta-lactam antibiotic.

4.4 Special warnings and precautions for use

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome and drug rash with eosinophila and systemic symptoms (DRESS) have been reported in some patients on cefixime. When severe cutaneous adverse reactions occur, cefixime should be discontinued and appropriate therapy and/or measures should be taken.

Hypersensitivity

Cefixime should be given with caution to patients who have shown hypersensitivity to other drugs.

Hypersensitivity to penicillins

Cephalosporins should be given with caution to penicillin-sensitive patients, as there is some evidence of partial cross-allergenicity between the penicillins and cephalosporins.

Patients have had severe reactions (including anaphylaxis) to both classes of drugs. Special care is indicated in patients who have experienced any allergic reaction to penicillins or any other beta-lactam antibiotics as cross-reactions may occur (for contraindications due to known hypersensitivity reactions see section 4.3).

If severe hypersensitivity reactions or anaphylactic reactions occur after administration of cefixime, the use of cefixime should be discontinued immediately and appropriate emergency measures should be initiated.

Acute renal failure

As with other cephlosporins, cefixime may cause acute renal failure including tubulointerstitial nephritis as an underlying pathological condition. When acute renal failure occurs, cefixime should be discontinued and appropriate therapy and/or measures should be taken.

Renal impairment

Cefixime should be administered with caution in patients with creatinine clearance < 20 ml / min (see sections 4.2 and 5.2). There are insufficient data regarding use of cefixime in the paediatric and adolescent age group in the presence of renal insufficiency. Therefore, the use of cefixime in these patient-groups is not recommended (see section 4.2).

Renal function is to be monitored under a combination therapy with cefixime preparations and aminoglycoside antibiotics, polymyxin B, colistin or high-dose loop diuretics (e.g. furosemide) because of the probability of additional renal impairment. This applies particularly for patients with already restricted renal function (see section 4.5).

Pseudomembranous colitis

Treatment with broad spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated diarrhoea. Pseudomembranous colitis is associated with the use of broad-spectrum antibiotics (including macrolides, semi-synthetic penicillins, lincosamides and cephalosporins); it is therefore important to consider its diagnosis in patients who develop diarrhoea in association with the use of antibiotics. Symptoms of pseudomembranous colitis may occur during or after antibiotic treatment.

The use of cefixime should be discontinued.

Management of pseudomembranous colitis should include sigmoidoscopy, appropriate bacteriologic studies, fluids, electrolytes and protein supplementation. If the colitis does not improve after the drug has been discontinued, or if the symptoms are severe, oral vancomycin is the drug of choice for antibiotic-associated pseudomembranous colitis produced by C. difficile. Other causes of colitis should be excluded. The use of medicinal products inhibiting the intestinal peristalsis is contraindicated.

Paediatric population

Safety of cefixime in premature or newborn infant has not been established (see section 4.2).

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant intake with potentially nephrotoxic substances (such as aminoglycoside antibiotics,colistin, polymyxin and viomycin) and strong-acting diuretics (e.g. ethacrynic acid or furosemide) induce an increased risk of impairment of renal function (see section 4.4).

Nifedipine, a calcium channel blocker, may increase bioavailability of cefixime up to 70 %.

In common with other cephalosporins, increases in prothrombin time have been noted in a few patients. Care should therefore be taken in patients receiving anticoagulation therapy. Cefixime should be administered with caution to patients receiving coumarin-type anticoagulants, e.g. warfarin potassium. Since cefixime may enhance effects of the anticoagulants, prolonged prothrombin time with or without bleeding may occur.

Administration of cefixime may reduce the efficacy of oral contraceptives. It is therefore recommended to take supplemental non-hormonal contraceptive measures.

Influence on laboratory diagnostic tests:

A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets, but not with tests based on enzymatic glucose oxidase reactions.

A false positive direct Coombs’ test has been reported during treatment with cephalosporin antibiotics, therefore it should be recognised that a positive Coombs’ test may be due to the drug.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of cefixime in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development, parturition or postnatal development (see section 5.3). Cefixime should not be used in pregnancy unless considered essential by the physician.

Breast-feeding

It is unknown whether cefixime is excreted in human breast milk. Animal studies have shown excretion of cefixime in breast milk (see section 5.2). A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with cefixime should be made taking into account the benefit of breast-feeding to the child and the benefit of cefixime therapy to the woman. However, until further clinical experience is available, cefixime should not be prescribed to breast-feeding mothers.

4.7 Effects on ability to drive and use machines

Cefixime has no known influence on the ability to drive and use machines. However, side effects may occur (see also section 4.8), which may influence the ability to drive and use machines.

4.8 Undesirable effects

In this section, the following convention has been used for the classification of undesirable effects in terms of frequency:

•    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)

•    Not known (cannot be estimated from the available data)

System Organ Class	Adverse Drug Reaction	Frequency
Infections and infestations	Superinfection bacterial, superinfection fungal	Rare
	Pseudomembranous- colitis	Very rare

Blood and lymphatic system disorders	Eosinophilia	Rare
	Leucopenia, agranulocytosis, pancytopenia, thrombocytopenia, haemolytic anaemia	Very rare
	Hypereosinophilia, thrombocytosis, neutropenia, granulocytopenia	Not known
Immune system disorders	Hypersensitivity	Rare
	Anaphylactic shock, serum sickness-like reaction,	Very rare
Metabolism and nutrition	Anorexia	Rare
disorders
Nervous system disorders	Headache	Uncommon
	Vertigo	Rare
	Psychomotor hyperactivity	Very rare
	Dizziness	Not known
Respiratory, thoracic and	Dyspnoea	Not known
mediastinal disorders
Gastrointestinal disorders	Diarrhoea*	Common
	Abdominal pain, nausea, vomiting	Uncommon
	Flatulence	Rare
	Dyspepsia	Not known
Hepatobiliary disorders	Hepatitis, cholestatic jaundice	Very rare
Skin and subcutaneous tissue	Rash	Uncommon
disorders	Angioneurotic oedema, pruritus	Rare
	Stevens-Johnson syndrome, toxic epidermal necrolysis drug rash with eosinophilia and systemic symptoms (DRESS), drug fever	Very rare

	Erythema multiforme, urticaria, face oedema	Not known
Musculoskeletal and connective tissue disorders	Arthralgia	Not known
Renal and urinary disorders	Renal failure acute including tubulointerstitial nephritis as an underlying pathological condition	Very rare
Reproductive system and breast disorders	Genital pruritus, vaginitis	Not known
General disorders and administration site conditions	Mucosal inflammation, pyrexia	Rare
Investigations	Hepatic enzyme increased (aspartate aminotransferase increased, alanine aminotransferase increased,, alkaline phosphatase)	Uncommon
	blood urea increased	Rare
	blood creatinine increased	Very rare
	Blood bilirubin increased	Not known

*Diarrhoea has been more commonly associated with higher doses. Some cases of moderate to severe diarrhoea have been reported; this has occasionally warranted cessation of therapy. Cefixime should be discontinued if marked diarrhoea occurs.

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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There is no experience with overdoses with cefixime.

Adverse reactions seen at dose levels up to 2 g cefixime in normal subjects did not differ from the profile seen in patients treated at the recommended doses. Cefixime is not removed from the circulation in significant quantities by dialysis.

No specific antidote exists. General supportive measures are recommended.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials, third-generation cephalosporins, ATC code: J01DD08

Mechanism of action

Cefixime is an antibacterial agent of the cephalosporin class. Like other cephalosporins, cefixime exerts antibacterial activity by binding to and inhibiting the action of penicillin-binding proteins involved in the synthesis of bacterial cell walls. This leads to bacterial cell lysis and cell death.

Pharmacokinetic/Pharmacodynamic relationship

The time that the plasma concentration of cefixime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in PK/PD studies.

Mechanisms of resistance

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

•    Hydrolysis by extended-spectrum beta-lactamases and / or by chromosomally-encoded (AmpC) enzymes that may be induced or de-repressed in certain aerobic gram-negative bacterial species

•    Reduced affinity of penicillin-binding proteins

•    Reduced permeability of the outer membrane of certain gram-negative organisms restricting access to penicillin-binding proteins

•    Drug efflux pumps

More than one of these mechanisms of resistance may co-exist in a single bacterial cell. Depending on the mechanism(s) present, bacteria may express cross-resistance to several or all other beta-lactams and / or antibacterial drugs of other classes.

Breakpoints

Clinical minimum inhibitory concentration (MIC) breakpoints established by EUCAST (May 2009) for cefixime are:

H. influenzae: sensitive < 0.12 mg/L, resistant > 0.12 mg/L

M. catarrhalis: sensitive < 0.5 mg/L, resistant > 1.0 mg/L

Neisseria gonorrhoeae: sensitive < 0.12 mg/L, resistant > 0.12 mg/L

Enterobacteriaceae: sensitive < 1.0 mg/L, resistant > 1.0 mg/L (for uncomplicated urinary tract infections only). The breakpoints for Enterobacteriaceae will detect reduced susceptibility mediated by most clinically important beta-lactamases in Enterobacteriaceae. Occasional ESBL-producing strains will be reported susceptible. For purposes of infection control, epidemiology and surveillance, laboratories may wish to use specific tests to screen for and confirm ESBL-production.

Non-species related breakpoints: insufficient data.

Legionella pneumophila Mycoplasma spp.

Pseudomonas species Staphylococcus aureus⁺

Streptococcus pneumoniae (Penicillin-intermediate and -resistant)

+ Cefixime has poor activity against staphylococci (regardless of susceptibility to methicillin)

$ Natural intermediate susceptibility.

% Extended spectrum beta-laktamase (ESBL) producing strains are always resistant.

& Resistance rate <10% in isolates of female patients with uncomplicated cystitis-otherwise >10%.

5.2 Pharmacokinetic properties

Absorption

The absolute oral bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly modified by the presence of food. Cefixime may therefore be given without regard to meals.

Distribution

Serum protein binding is well characterised for human and animal sera; cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of cefixime is only concentration dependent in human serum at very high concentrations, which are not seen following clinical dosing.

From in vitro studies, serum or urine concentrations of 1 mg/L or greater were considered to be adequate for most common pathogens against which cefixime is active. Typically, the peak serum levels following the recommended adult or paediatric doses are between 1.5 and 3 mg/L. Little or no accumulation of cefixime occurs following multiple dosing.

Biotransformation and elimination

Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.

Transfer of ¹⁴C-labelled cefixime from lactating rats to their nursing offspring through breast milk was quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data are available on secretion of cefixime in human breast milk. Placental transfer of cefixime was small in pregnant rats dosed with labelled cefixime.

Pharmacokinetic/pharmacodynamics relationships

The pharmacokinetics of cefixime in healthy elderly (age > 64 years) and young volunteers (11-35) compared the administration of 400 mg doses once daily for 5 days. Mean C_max and AUC values were slightly greater in the elderly. Elderly patients may be given the same dose as the general population.

5.3 Preclinical safety data

There are no findings from chronic toxicity investigations suggesting that any side effects unknown to date could occur in humans. Furthermore, in vivo and in vitro studies did not yield any indication of a potential to cause mutagenicity. Long-term studies on carcinogenicity have not been conducted. Reproduction studies have been performed in mice and rats at doses up to 400 times the human dose and have revealed no evidence of impaired fertility or harm to the foetus due to cefixime. In the rabbit, at doses up to 4 times the human dose, there was no evidence of a teratogenic effect; there was a high incidence of abortion and maternal death, which is an expected consequence of the known sensitivity of rabbits to antibiotic-induced changes in the population of the microflora of the intestine.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Cellulose, microcrystalline Starch, pregelatinised Calcium hydrogen phosphate, anhydrous Magnesium stearate.

Silica, colloidal anhydrous

Hypromellose Titanium dioxide (E 171)

Macrogol 400

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

24 months.

6.4    Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package.

6.5    Nature and contents of container

PVC/ PVdC/ Aluminium blister pack: 3, 5, 7, 10 & 100.

PVC/Aclar/ Aluminium blister pack: 3, 5, 7, 10 & 100.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Not applicable.

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

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1308

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

16/12/2010

10 DATE OF REVISION OF THE TEXT

22/01/2015

12