Document: spc-doc_PL 40168-0002 change

• spc-doc_PL 22805-0032
• spc-doc_PL 40168-0002

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Cefixime 400 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains 400 mg cefixime (as cefixime trihydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

*Film-coated tablet.

White to slightly cream, oblong, biconvex film-coated tablets with bisection line on one side of the tablet.

The tablet can be divided into equal doses.

The dimensions of each tablet are approximately 20.0 mm x 8.0 mm.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Cefixime is indicated for the treatment of the following infections caused by susceptible microorganisms (see section 5.1.):

Acute exacerbations of chronic bronchitis (AECB)

Acute otitis media Uncomplicated acute cystitis Uncomplicated pyelonephritis.

4.2    Posology and method of administration

Posology

Adults: The recommended adult dosage is 400 mg daily, given either as a single dose or in two divided doses of 200 mg every 12 hours.

Older people

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 “Dosage in Renal Impairment”) (see above and section 4.4.).

Adolescents 12 years of age and older

should be treated with the recommended adult dose (400 mg daily, given either as a single dose or in two divided doses of 200 mg every 12 hours).

Children younger than 12 years of age

The pharmaceutical form tablet is not suitable for children younger than 12 years.

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 pediatric and adolescent age groups in the presence of renal insufficiency. Therefore, the use of cefixime in these patient-groups is not recommended.

Duration of treatment

The usual course of treatment is 7 days. This may be continued for up to 14 days according the severity of the infection.

For acute uncomplicated cystitis in women, the treatment period is 1-3 days.

Method of administration

Cefixime tablets are for oral administration only. Cefixime 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, to other cephalosporin antibiotic 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

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

Renal insufficiency

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 pediatric and adolescent age group in the presence of renal insufficiency. Therefore, the use of cefixime in these patient-groups is not recommended.

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).

Treatment with cefixime at the recommended (400 mg) dose can significantly alter the normal flora of the colon and lead to overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of antibiotic-associated diarrhoea. In patients who develop severe persistent diarrhoea

during or after use of cefixime, the risk of life threatening pseudomembranous colitis should be taken into account. The use of cefixime should be discontinued and appropriate treatment measures should be established. The use of medicinal products inhibiting the intestinal peristalsis is contraindicated (see section 4.8).

Prolonged use of cefixime may result in the overgrowth of non-susceptible organisms.

Severe skin reactions such as drug hypersensitivity syndrome (DRESS) or bullous skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome) have been reported in patients treated with cefixime (see section 4.8). If such reactions occur, cefixime should be immediately stopped.

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 times have been noted in a few patients. Care should therefore be taken in patients receiving anticoagulation therapy.

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.

A false-positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide.

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/ fetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, Cefixime should not be used in pregnant mothers unless considered essential by the physician.

Breast-feeding

It is unknown whether cefixime is excreted in human milk. Non-clinical studies have shown excretion of cefixime in animal milk. A decision on whether to continue/discontinue breastfeeding 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.

Fertility

Reproduction studies performed in mice and rats do not indicate harmful effects with respect to fertility (see section 5.3.).

4.7 Effects on ability to drive and use machines

Cefixime has no known influence on 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:

•    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 >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)
Infections and infestations			Superinfection bacterial, superinfection fungal	Antibiotic-associated colitis (see section 4.4.)
Blood and lymphatic system disorders			Eosinophilia	Leucopenia, agranulocytosis, pancytopenia, thrombocytopenia, haemolytic anaemia	Thrombocyt osis, neutropenia
Immune system disorders			Hypersensitivity	Anaphylactic shock, serum sickness

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, Website: www.mhra.gov.uk/yellowcard.

Overdose

There is no experience with cefixime overdose.

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. Gastric lavage may be indicated in overdosage. No specific antidote exists. Cefixime is not removed from the circulation in significant quantities by hemodialysis or peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 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.

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 (January 2013) 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).

•    Non-species related breakpoints: insufficient evidence

*Isolates with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC values above the current resistant breakpoint they should be reported resistant.

Susceptibility

The prevalence of resistance may vary geographically and over 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 the agent in at least some types of infections is questionable.

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 mcg/ml 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 mcg/ml. Little or no accumulation of cefixime occurs following multiple dosing.

Biotransformation and, elimination

The pharmacokinetics of cefixime in healthy elderly (age > 64 years) and young volunteers (1135) compared the administration of 400 mg doses once daily for 5 days. Mean Cmax and AUC values were slightly greater in the elderly. Elderly patients may be given the same dose as the general population (see section 4.2).

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/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.

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 fetus 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

Tablet core:

Microcrystalline Cellulose;

Calcium hydrogen phosphate dihydrate;

Starch, pregelatinized;

Magnesium stearate.

Film-coating:

Hypromellose 5 cP E464;

Macrogol 400;

Titanium dioxide E171.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The film coated tablets are blister-packed in transparent PVC/PVDC/Al foil. Each blister contains 5 tablets or 7 tablets.

The lithographed cardboard carton contains 1 blister with 5 tablets (5 tablets) or 1 blister with 7 tablets (7 tablets) or 2 blisters with 5 tablets (10 tablets) and a leaflet inside.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

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

7    MARKETING AUTHORISATION HOLDER

INN-FARM d.o.o.

Maleseva ulica 014 1000 Ljubljana Slovenia

8 MARKETING AUTHORISATION NUMBER(S)

PL 40168/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/09/2013

10 DATE OF REVISION OF THE TEXT

06/04/2016