Midixime^® 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.

·       Community-acquired Pneumonia.

·       Lower urinary tract infections.

·       Pyelonephritis.

In the treatment of:

·       Otitis media.

·       Sinusitis.

·       Pharyngitis

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

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

Midixime^® 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:

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

Midixime^® 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 Midixime^®/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).

One plastic oral syringe (5 ml) contains the equivalent of 100 mg Midixime^®.

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

Hypersensitivity to penicillins

Midixime^® 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 Midixime^®, the use of Midixime^® should be discontinued immediately and appropriate emergency measures should be initiated.

Patients with impaired renal function

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

Pseudomembranous colitis

Treatment with Midixime^® 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 diarrhea. In patients who develop severe persistent diarrhea during or after use of Cefixime, the risk of life threatening pseudomembranous colitis should be taken into account. The use of Midixime^® 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 Midixime^® 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, Midixime^® should be immediately stopped.

Paediatric use

Midixime^®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 Midixime^® 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 Midixime^® 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.

Midixime^® 100 mg/5 ml Dry suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or

sucrase-isomaltase insufficiency should not take this medicine.

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.

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 Midixime^® should be made taking into account the benefit of breast-feeding to the child and the benefit of Midixime^® therapy to the woman. However, until further clinical experience is available, Midixime^® 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.).

Midixime^® has no known influence on the ability to drive and use machines.

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).

To report any side effect(s):

•Saudi Arabia:

The National Pharmacovigilance Center (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

•Other GCC States:

Please contact the relevant competent authority.

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.

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 chromosomallyencoded (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.

Commonly susceptible species

Aerobes, Gram positive:

Streptococcus pyogenes

Aerobes, Gram negative:

Haemophilus influenzae

Moraxella catarrhalis

Proteus mirabilis^%

Species for which resistance may be a

problem

Aerobes, Gram negative:

Citrobacter freundii ^$

Enterobacter cloacae ^$

Escherichia coli ^{% &}

Klebsiella oxytoca ^%

Klebsiella pneumoniae ^%

Morganella morgani ^$

Serratia marcescens ^$

Inherently Resistant species

Aerobes, Gram positives:

Enterococci

Streptococcus pneumoniae

Staphylococcus spp.

Aerobes, Gram-negative

Pseudomonas species

Other micro-organism

Chlamydia spp.

Chlamydophila spp.

Clostridium difficile

Bacteroides fragilis

Legionella pneumophila

Mycoplasma spp.

^$ 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%.

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 labeled Cefixime.

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.

Sucrose, sodium benzoate, xanthan gum, strawberry powder flavor, colloidal anhydrous silica.

None.

Midixime^® 100mg/5ml Dry Suspension: Store below 30°C.

Midixime^® Dry Suspension is maintaining its chemical, physical and microbiological specification within the limits after daily opening for 14 days when stored at temperature below 30 °C. The product is safe and effective during use by final user.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Midixime^® 100mg/5ml Dry Suspension: is off-white to slightly yellow, flowable, strawberry flavored powder.

After reconstitution: result in a suspension with off-white to slightly yellow, strawberry flavored, presented in amber glass bottle Type III with white opaque Polypropylene CRC Cap, intended for oral use.

Pack size: 60 ml.

None stated.