Mixif® is an orally active cephalosporin antibiotic which has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms.
Cefixime is indicated for the treatment of the following infections when caused by susceptible organisms:
• Acute exacerbations of chronic bronchitis
• Community-acquired Pneumonia
• Lower urinary tract infections
• Pyelonephritis
• Otitis media
• Sinusitis
• Pharyngitis
The use of Cefixime should be reserved for infections where the causative organism is known or suspected to be resistant to other commonly used antibiotics, or where treatment failure may carry significant risk.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Adults and children over 10 years of age (body weight is greater than 50 kg)
The recommended dose is 200-400 mg daily according to the severity of the infection, given either as a single dose or in two divided doses.
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 impairment (See dosage for renal impairment and section 4.4).
Children younger than 10 years of age (body weight is lower than 50 kg) –
Paediatric Oral Suspension
The recommended dosage for children is 8 mg/kg/day administered as a single dose or in two divided doses. The following table describes a range of paediatric dosage according to the weight of the child:
Children weighing more than 50 kg or older than 10 years should be treated with the recommended adult dose (200 -400 mg daily), depending on the severity of the infection.

Child’s weight	Daily dose	Daily dose according to the syringe graduations
5 kg	40 mg	2 ml (once daily) or 1 ml (twice daily)
10 kg	80 mg	4 ml (once daily) or 2 ml (twice daily)
12.5 kg	100 mg	5 ml (once daily) or 2.5 ml (twice daily)
15 kg	120 mg	6 ml (once daily) or 3 ml (twice daily)
17.5 kg	140 mg	7 ml (once daily) or 3.5 ml (twice daily)
20 kg	160 mg	8 ml (once daily) or 4 ml (twice daily)
22.5 kg	180 mg	9 ml (once daily) or 4.5 ml (twice daily)
25 kg	200 mg	10 ml (once daily) or 5 ml (twice daily)

Children weighing more than 50 kg or older than 10 years should be treated with the recommended adult dose (200 -400 mg daily), depending on the severity of the infection.
Children younger than 6 months of age
The safety and efficacy of cefixime has not been established in children less than 6 months.
Renal impairment
Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be given in patients with creatinine clearance 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 dialysis or haemodialysis should follow the same recommendation as that for patients with creatinine clearance of less than 20 ml/min.
Method of administration
Cefixime powder for oral suspension is for oral administration only.
The absorption of cefixime is not significantly affected by the presence of food.
Hence it can be administered with or without food. For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Duration of treatment
The usual course of treatment is 7 days. In severe cases, this can be extended to 14 days.

 

Patients with known hypersensitivity to cephalosporin antibiotics or any of the other components of the product. Cefixime is also contraindicated in patients with previous, immediate and/or severe hypersensitivity to penicillin or any beta-lactam antibiotics and preterm and term newborn infants (0-27 days).

Severe cutaneous adverse reactions
Severe cutaneous adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome and drug rash with eosinophilia 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.
Mixif® should be given with caution to patients who have shown hypersensitivity to other drugs.
Hypersensitivity to penicillins
As with other cephalosporins, cefixime should be given with caution to patients with a history of hypersensitivity to penicillin, 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. If severe hypersensitivity reactions or anaphylactic reactions occur after administration of Cefixime, the medicine should be discontinued immediately and appropriate emergency measures should be initiated.
Haemolytic anaemia
Drug-induced haemolytic anaemia, including severe cases with a fatal outcome, has been described for cephalosporins (as a class). The recurrence of haemolytic anaemia after re-administration of cephalosporins in a patient with a history of cephalosporin (including cefixime) –associated haemolytic anaemia has also been reported.
Antibiotic associated pseudomembreanous colitis produced by C. Difficile.
Prolonged use of cefixime may result in the overgrowth of non-susceptible organisms.
Treatment with a broad spectrum of antibiotics alters the normal flora of the colon and may permit the overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause for 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.
In patients who develop severe diarrhoea during or after use of cefixime, the risk of life threatening pseudo-membranous colitis should be taken into account (see section 4.8). The use of cefixime should be discontinued and appropriate treatment measures should be established. Management of pseudomembranous colitis should include sigmoidoscopy, appropriate bacteriologic studies, fluids, electrolyte 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 pseudomembreanous colitis produced by C. Difficile. Other causes of colitis should be excluded. The use of medicinal products inhibiting the intestinal peristalsis is contra-indicated.
Acute renal failure
As with other cephalosporins, 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.
Use of Nifedipine, a calcium channel blocker, may increase bioavailability of Cefixime up to 70%.
Renal insufficiency
Cefixime should be administered with caution in adult patients with creatinine clearance <20ml/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: the use of cefixime in these patient-groups is not recommended.
Paediatric use
Safety of cefixime in premature or newborn infant has not been established.
Mixif® suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Anticoagulants
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.
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.
In use with Nifedipine, a calcium channel blocker, may increase bioavailability of
Cefixime up to 70%.
Other forms of interaction
The administration of cephalsporins may interfere with the results of some laboratory
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.

Pregnancy
For cefixime, no clinical data on exposed pregnancies are available. 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).
Caution should be exercised when prescribing to pregnant women. 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 and 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
Animal studies do not indicate any harmful effects with respect to fertility, however, no clinical data are available

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

Cefixime is generally well tolerated. The majority of adverse reactions observed in clinical trials were mild and self-limiting in nature.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following undesirable effects have been divided in the following categories:
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
Not known: cannot be estimated from the available data

System Organ Class	Adverse Reaction	Frequency
Infections and infestations	Superinfection bacterial, superinfection fungal	Rare
		Very rare
Blood and lymphatic system disorders	Eosinophilia	Rare
	Leucopenia, agranulocytosis, pancytopenia, thrombocytopenia, haemolytic anaemia	Very rare
Immune system disorders	Hypersensitivity	Rare
	Anaphylactic shock, serum sickness	Very rare
Metabolism and nutrition disorders	Anorexia	Rare
Nervous system disorders	Headache	Uncommon
	Vertigo, dizziness	Rare
	Psychomotor hyperactivity	Very rare
Gastrointestinal disorders	Diarrhoea*	Common
	Abdominal pain, nausea, vomiting	Uncommon
	Flatulence	Rare
	Cases of pseudomembraneous colitis	Very rare
Hepatobiliary disorders	Hepatitis, cholestatic jaundice	Very rare
Skin and subcutaneous disorders	Rash	Uncommon
	Angioneurotic oedema, pruritus	Rare
	Stevens-Johnson Syndrome, toxic epidermal necrolysis, Lyell syndrome	Very rare
Renal and urinary disorders	Interstitial nephritis	Very rare
General disorders and administration site conditions	Mucosal inflammation, pyrexia	Rare
Investigations	Hepatic enzyme increased (transaminase, alkaline phosphatase)	Uncommon
	Blood urea increased	Rare
	Blood creatinine increased	Very rare

*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. Mixif® should be discontinued if marked diarrhoea occurs.
To report any side effects:
National Pharmacovigilance &amp; amp; Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

 

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.

Pharmacotherapeutic group: antibacterial for systemic use, belonging to the class of
cephalsporins, ATC code: J01DD08.
Mode of action
Cefixime is an antibiotic belonging to the third-generation cephalosporin group. Like other cephalsporins, 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.
Mechanism 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 gramnegative 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 beta-lactams and/or antibacterial drugs of other classes.
Breakpoints
Clinical minimum inhibitory concentration (MIC) breakpoints established by EUCAST (May 2009) for cefixime are:
Breakpoints (MIC, mg/L)

Microorganism Susceptible (≤)	Susceptible (≤)	Resistant (>)
Haemophilus influenzae	0.12 mg/L	0.12 mg/L
Moraxella catarrhalis	0.5 mg/L	1.0 mg/L
Neisseria gonorrhoeae	0.12 mg/L	0.12 mg/L
Enterobacteriaceae	1.0 mg/L	1.0 mg/L
Enterobacteriaceae: For uncomplicated urinary tract infections only. The breakpoints for Enterobacteriaceae will detect reduced susceptibility mediated by most clinically important beta-lactamases in Enterobacteriaceae. Occassional 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

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 local
prevalence if resistance is such that the utility of the agent in at least some types of
infections is questionable.

Category 1: Commonly Susceptible organisms
Aerobes, Gram-positive	Aerobes, Gram-negative
Streptococcus pneumoniae (penicillinsusceptible) Streptococcus pyogenes	Escherichia Coli% Haemophilus influenzae Klebsiella species% Morexella catarrhalis Proteus mirabilis%
Category 2: Organisms for which acquired resistance may be problematic Enterobacter species
Category 3: Resistant organisms Clostridium difficile Bacteroides fragilis Enterococci Pseudomonas species Staphylococcus aureus+ Streptococcus pneumoniae (Penicillin resistant) Enterobacter species
% Extended spectrum beta-lactamase (ESBL) producing isolates are always resistant
+ Cefixime has poor activity against staphylococci (regardless of susceptibility to methicillin)

Absorption
The absolute 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 for 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.
Metabolism 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.
Special age groups
The pharmacokinetics of cefixime in healthy elderly (aged > 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

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 does 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 hypersensitivity of rabbits to antibiotic-induced changes in
the population of the microflora of the intestine.

Sodium benzoate, silica colloidal anhydrous, xanthan gum, sucrose, tutti frutti flavor.

None.

24 months

Store below 30°C. Discard unused content 14 days after reconstitution.

Mixif suspension is available in bottles for preparing 60 ml or 30 ml flavored
suspensions. These bottles contain off white to yellowish powder. Comes with a
measuring spoon that can measure 2.5ml and 5ml.

Any unused product or waste material should be disposed of in accordance with local requirements.
For reconstitution of Mixif suspension:
− Invert the bottle and shake content to loosen powder, add pre-boiled cooled water to the mark, and shake well, then add more water if necessary up to the mark and shake well until a homogeneous suspension is obtained
− When first reconstituted, allow to stand for five minutes to ensure full dispersion
− Shake the bottle well before use