SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cefixime 100 mg/5 ml granules for oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of reconstituted oral suspension contains 111.9 mg of cefixime trihydrate equivalent to 100 mg of cefixime (anhydrous).

Excipients with known effect:

Sucrose 2517.40 mg/5 ml Sodium benzoate E 211

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Granules for oral suspension Almost white to pale yellow granules.

The reconstituted suspension is an almost white to pale yellow viscous liquid.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Cefixime is indicated for the treatment of the following infections caused by susceptible microorganisms in children above 6 months, adolescents and adults (see section 5.1.):

Acute exacerbations of chronic bronchitis (AECB) Acute otitis media Uncomplicated acute cystitis Uncomplicated pyelonephritis.

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

4.2 Posology and method of administration

Posology

Adults and teenagers

400 mg once daily (= 20 ml of the reconstituted suspension) as a single dose or 2 times daily 200 mg (= 10 ml) at intervals of 12 hours.

Elderly

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.).

Children under 12 years

Cefixime 8 mg / kg body weight / day, either as a single dose or two divided doses 12 hourly.

The dosing recommendations are given in the following table:

Body weight	Daily dose (ml) Once daily	Daily dose (ml) Twice daily	Daily dose (mg)
6.0 kg-9 kg (for infants above 6 months)	1 x 2.5 ml	2 x 1.25 ml	50 mg
10.0 kg	4 ml	2 x 2 ml	80 mg
12.5 kg	5 ml	2 x 2.5 ml	100 mg
15.0 kg	6 ml	2 x 3 ml	120 mg
17.5 kg	7 ml	2 x 3.5 ml	140 mg
20.0 kg	8 ml	2 x 4 ml	160 mg
22.5 kg	9 ml	2 x 4.5 ml	180 mg
25.0 kg	10 ml	2 x 5 ml	200 mg
27.5 kg	11 ml	2 x 5.5 ml	220 mg
30.0 kg	12 ml	2 x 6 ml	240 mg
37.5 kg	15 ml	2 x 7.5 ml	300 mg
>37.5 kg	20 ml	2 x 10 ml	400 mg

For adolescents and adults without swallowing problems, the use of cefixime tablets is recommended.

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

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/1.73 m², it is recommended that a dose of 200 mg once daily should not be exceeded. In children under 12 years with a creatinine clearance of <20 ml/min/1.73 m2, a dose of 4 mg cefixime/kg body weight should be given only once a day. 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.

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

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Cefixime 100 mg/5 ml granules for oral suspension is for oral administration only. The reconstituted suspension should be administered undiluted before or during a meal (see section 5.2).

A plastic oral syringe (5 ml) is provided with the bottle to aid correct dosing. One plastic oral syringe (5 ml) contains the equivalent of 100 mg cefixime.

Absorption of cefixime is not significantly modified by the presence of food.

4.3 Contraindications

Hypersensitivity to the active substance, 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

Hypersensitivity to penicillins

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.

Patients with impaired renal function

Cefixime should be administered with caution in patients with creatinine clearance < 20 ml / min (see sections 4.2 and 5.2).

Pseudomembranous colitis

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 cutaneous adverse reactions

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.

Paediatric use

Cefixime should not be administered to preterm new-borns and new-borns.

Administration with other medicinal products

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).

The use of cefixime may lead to vomiting and diarrhea (see section 4.8). In this case, the efficacy of this and/ or other ingested medicinal products (such as oral contraceptives) may be impaired.

Cefixime 100 mg/5 ml granules for oral suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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 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.

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	Commo n >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	Thrombocytosis , neutropenia
Immune system disorders			Hypersensitivit y	Anaphylactic shock, serum sickness
Metabolism and nutrition disorders			Anorexia
Nervous system disorders		Headache	Vertigo	Psychomotor hyperactivity
Gastrointestina l disorders	Diarrhoe a	Abdominal pain, nausea, vomiting	Flatulence

Hepatobiliary disorders				Hepatitis, cholestatic jaundice
Skin and subcutaneous tissue disorders		Rash	Angioneurotic oedema, pruritus	Stevens-Johnson syndrome, toxic epidermal necrolysis	Drug rash with eosinophilia and systemic symptoms (DRESS) (see section 4.4.), erythema multiforme
Renal and urinary disorders				Interstitial nephritis
General disorders and administration site conditions			Mucosal inflammation, pyrexia
Investigations		Hepatic enzyme increased (transaminase , alkaline phosphatase)	Blood urea increased	Blood creatinine increased	Direct and indirect positive Coombs tests (see section 4.4)

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.

4.9 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

Pharmaco-therapeutic 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.

PK/PD 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 (January 2015) 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

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.

$ Natural intermediate susceptibility.

% Extended spectrum beta-lactamase (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 40-50%. 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 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 (11-35) 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.

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

Sucrose

Xanthan gum

Sodium benzoate E 211

Flavour durarome orange containing: Flavouring ingredients Maltodextrin Sucrose

Soy-Lecithin E322 Silicon dioxide E551

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Unreconstituted product: 2 (two) years.

Reconstituted suspension: The reconstituted suspension may be stored for 14 days at ambient conditions (below 25^oC) or refrigerated conditions.

6.4 Special precautions for storage

Unreconstituted product should be stored below 25^oC.

For storage conditions of the reconstituted product, see section 6.3.

6.5 Nature and contents of container

The granules for oral suspension is immediate packed in a 150 ml brown neutral glass bottle Ph.Eur. Type III, supplied with an aluminium screw cap with a polyethylene sealing.

Cardboard box contains one (1) bottle, one plastic (polypropylene) measuring cup for reconstitution only graduated on 40 ml or 66 ml, one plastic graduated oral syringe for dosing, and an instruction leaflet. Each bottle contains 32 g granules for preparation of 60 ml oral suspension or 53 g granules for preparation of 100 ml oral suspension. The 5 ml plastic (polyethylene-polystyrene) oral syringe with scale from 0.5 ml to 5 ml is graduated on each 0.25 ml imprinted on the plunger of the syringe for measuring of the doses.

6.6 Special precautions for disposal

Preparation of the suspension:

60 ml oral suspension: To reconstitute, use the plastic measuring cup provided in the cardboard box. Add 40 ml of water in two portions shaking after each addition.

100 ml oral suspension: To reconstitute, use the plastic measuring cup provided in the cardboard box. Add 66 ml of water in two portions shaking after each addition.

Shake the medicine bottle well before each use.

A graduated plastic oral syringe is used for measuring the required prescribed amount of suspension. The plastic oral syringe is included in the package.

No special requirements for disposal.

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

7 MARKETING AUTHORISATION HOLDER

INN-FARM d.o.o.

Maleseva ulica 14 1000 Ljubljana Slovenia

8    MARKETING AUTHORISATION NUMBER(S)

PL 40168/0005

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/04/2015

10    DATE OF REVISION OF THE TEXT

15/04/2015