Cefpodoxime Proxetil 40mg/5ml Powder For Oral Suspension

Document: spc-doc_PL 04520-0138 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cefpodoxime Proxetil 40 mg/5 ml Powder for Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

5 ml of reconstituted suspension contains cefpodoxime proxetil corresponding to 40 mg cefpodoxime.

Excipients with known effect:

5 ml of reconstituted suspension contain 1845,78 mg sucrose and 25.00 mg Aspartame.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral suspension

Cream-tinged to orange-yellow powder; after reconstitution with water resulting in an orange-yellow suspension.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Cefpodoxime Proxetil 40mg/5ml Powder for Oral Suspension is indicated for the treatment of the following infections when caused by susceptible organisms.

- Acute otitis media

- Sinusitis

- Tonsillitis and pharyngitis

In these indications, cefpodoxime should be reserved for recurrent or chronic infections, or for infections where the causative organism is known or suspected to be resistant to commonly used antibiotics or in case the commonly used antibiotic cannot be used for any reason.

- Acute bronchitis

- Bacterial pneumonia

Cefpodoxime is not the preferred antibiotic for the treatment of staphylococcal pneumonia and should not be used in the treatment of atypical pneumonia caused by organisms such as Legionella, Mycoplasma and Chlamydia (see also section 5.1).

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

4.2 Posology and method of administration

Posology

Children(up to 11 years):

The recommended dose for children is 8mg/kg/day administered in two divided doses at 12-hour intervals. A syringe (10ml) with 0.5 ml marked graduations is provided with the bottle to aid correct dosing.

Note that:

5 ml of suspension contains the equivalent of 40 mg cefpodoxime.

1 ml of suspension contains the equivalent of 8 mg cefpodoxime.

The following table provides a guide to prescribing:

Body weight in KG	Cefpodoxime dose in mg to be given twice daily	Cefpodoxime dose in ml of suspension to be given twice daily
5	20 mg	2.5 ml
10	40 mg	5 ml
15	60 mg	7.5 ml
20	80 mg	10 ml
25	100 mg	12.5 ml

Children who weigh at least 25 kg may receive 12.5 ml twice daily or may choose to receive a 100 mg tablet twice daily.

Cefpodoxime should not be used in infants less than 15 days old as there is no experience in this age group.

Renal Impairment:

The dose of Cefpodoxime does not require modification if creatinine clearance exceeds 40ml.min^-1/1.73m²

Below this value, pharmacokinetic studies indicate an increase in plasma elimination half-life. Therefore, the dose should be adjusted appropriately as shown in the table below.

CREATININE CLEARANCE (ML/MIN)
39 - 10	4 mg/kg should be administered once every 24 hours.
< 10	4 mg/kg should be administered once every 48 hours.
Haemodialysis Patients	4 mg/kg should be administered after each dialysis session.

Hepatic Impairment:

The dose does not require modification in cases of hepatic impairment. Duration

The duration of therapy depends on the patient, the indication and the causative pathogen(s).

Method of Administration

The suspension is for oral administration only.

Doses should be taken during meals for optimal absorption

4.3 Contraindications

Hypersensitivity to the active substance, to any of the cephalosporins or to any of the suspension excipients listed in section 6.1.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta-lactam drug.

4.4 Special warnings and precautions for use

Hypersensitivity reactions

Before therapy with cefpodoxime is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to cefpodoxime, cephalosporins, penicillins, or other beta-lactam drugs.

Cefpodoxime is contraindicated in patients who have had a previous hypersensitivity reaction to any cephalosporin.

It is also contraindicated in patients who have had a previous immediate and /or any severe hypersensitivity reaction to any penicillin or to any other beta-lactam drug.

Cefpodoxime should be given with caution to patients who have had any other type of hypersensitivity reaction to a penicillin or any other beta-lactam drug.

Hypersensitivity reactions (anaphylaxis) observed with beta-lactam antibiotics can be serious and occasionally fatal.The onset of any manifestation of hypersensitivity indicates that treatment should be stopped.

Renal Insufficiency

In cases of severe renal insufficiency it may be necessary to reduce the dose dependent on the creatinine clearance (see section 4.2).

Gastrointestinal disease

Cefpodoxime should always be used with caution in patients with a history of gastrointestinal disease, particularly colitis. Antibiotic associated diarrhoea, colitis and pseudomembranous colitis have been reported with the use of cefpodoxime. These diagnoses should be considered in any patient who develops diarrhoea during or shortly after treatment. Cefpodoxime should be discontinued if severe and/or bloody diarrhoea occurs during treatment and appropriate therapy instituted.

Blood monitoring

As with all beta-lactam antibiotics, neutropenia and more rarely agranulocytosis may develop particularly during extended treatment. For cases of treatment lasting longer than 10 days, the blood count should be monitored and treatment discontinued if neutropenia is found.

Cephalosporins may be absorbed onto the surface of red cell membranes and react with antibodies directed against the drug. This can produce a positive Coomb's test and very rarely, haemolytic anaemia. Cross-reactivity may occur with penicillin for this reaction.

Renal _ function

Changes in renal function have been observed with cephalosporin antibiotics, particularly when given concurrently with potentially nephrotoxic drugs such as aminoglycosides and/or potential diuretics. In such cases, renal function should be monitored.

Prolonged use

As with other antibiotics, the prolonged use of cefpodoxime proxetil may result in the overgrowth of non-susceptible organisms. With oral antibiotics the normal colonic flora may be altered, allowing overgrowth by clostridia with consequent pseudomembranous colitis. Repeated evaluation of the patient is essential and if superinfection occurs during therapy, appropriate measures should be taken.

Paediatric _ population

The product should not be used in infants less than 15 days old as no clinical trial data in this age group yet exists.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

5ml of the ready-to-use suspension of Cefpodoxime proxetil 40mg/5ml Powder for Oral Suspension contains 1.8g of sucrose. This should be taken into account in patients with diabetes mellitus.

Cefpodoxime proxetil 40mg/5ml Powder for Oral Suspension contains aspartame, a source of phenylalanine and may be harmful for people with phenylketonuria.

4.5 Interaction with other medicinal products and other forms of interaction

No clinically significant drug interactions have been reported during the course of clinical studies.

Histamine H₂-antagonists and antacids reduce the bioavailability of cefpodoxime. Probenecid reduces the excretion of cephalosporins. Cephlasporins potentially enhance the anticoagulant effect of coumarins and reduce the contraceptive effect of oestrogens.

Antacids and Ht_ blockers

Studies have shown that bioavailability is decreased by approximately 30% when cefpodoxime is administered with drugs which neutralise gastric pH or inhibit acid secretions. Therefore, such drugs as antacids of the mineral type and H2 blockers such as ranitidine, which can cause an increase in gastric pH, should be taken 2 to 3 hours after cefpodoxime administration.

Influence on laboratory diagnostic tests

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

4.6 Fertility, pregnancy and lactation

For cefpodoxime proxetil 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.

Studies carried out in several animal species have not shown any teratogenic or fetotoxic effects. However, the safety of cefpodoxime proxetil in pregnancy has not been established and, as with all drugs, it should be administered with caution during the early months of pregnancy.

Cefpodoxime is excreted in human milk. Mothers should stop breastfeeding during treatment with cefpodoxime.

4.7 Effects on ability to drive and use machines

Cefpodoxime proxetil has minor or moderate influence on the ability to drive and use machines.

Dizziness has been reported during treatment with cefpodoxime and may affect patients’ ability to drive or operate machinery.

4.8 Undesirable effects

In this section undesirable effects are defined as follows: 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)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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					There can be multiplication of non-sensitive microorganisms (see section 4.4).
Blood and lymphatic system disorders			Haematological disorders, such as reduction in haemoglobin, thrombocytosis, thrombocytopen ia, leucopenia and eosinophilia.	Haemolytic anaemia.
Immune system disorders
Hypersensitivity reactions of all degrees of severity have been observec 4.3 and 4.4).				(see section
		Allergic reactions, such as mucocutaneous reactions, skin rashes, urticaria and pruritus.		Dermal reactions with blistering (erythema multiforme, Stevens- Johnson syndrome, Lyell syndrome). The

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)
				medication should be terminated if such symptoms occur. As with other cephalosporins , there have been very rare reports of anaphylactic reactions, bronchospasm, purpura and angioedema.
Metabolism and nutrition disorders	Loss of appetite.
Nervous system disorders		Headaches, paraesthesiae, dizziness.
Ear and labyrinth disorders		Tinnitus.
Gastrointestina l disorders	Gastric pressure, nausea, vomiting, abdominal pain, flatulence, diarrhoea.		Bloody diarrhoea can occur as a symptom of enterocolitis. The possibility of pseudomembran ous enterocolitis should be considered if severe or persistent diarrhoea occurs during or after treatment (see section 4.4).
Hepato-biliary disorders			Transient moderate elevations of	Liver damage.

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)
			ASAT, ALAT and alkaline phosphatase and/or bilirubin. These laboratory abnormalities which may be explained by the infection, may rarely exceed twice the upper limit of the named range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.
Renal and urinary disorders				Slight increases in blood urea and creatinine.
General disorders and administration site conditions		Asthenia or malaise.

4.9 Overdose

In the event of overdose with cefpodoxime proxetil, supportive and symptomatic therapy is indicated.

In cases of overdose, particularly in patients with renal insufficiency, encephalopathy may occur. The encephalopathy is usually reversible once cefpodoxime plasma levels have fallen.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: P-lactam antibiotic, 3 generation cephalosporins

ATC classification: J01D D13

Mechanism of action

Like other P-lactam drugs, cefpodoxime exerts antibacterial activity by binding to and inhibiting the action of certain bacterial cell wall synthetic enzymes, namely the penicillin binding proteins. This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.

PK/PD relationship

Antibacterial efficacy of cefpodoxime mainly depends on the time period, in which its level is above the minimum inhibitory concentration (MIC).

Mechanisms of Resistance

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

- hydrolysis by beta-lactamases. Cefpodoxime may be efficiently hydrolysed by certain of the extended-spectrum beta-lactamases (ESBLs) and by the chromosomally-encoded (AmpC) enzyme that may be induced or stably derepressed in certain aerobic gram-negative bacterial species

- reduced affinity of penicillin-binding proteins for cefpodoxime

- outer membrane impermeability, which restricts access of cefpodoxime to penicillin binding proteins in gram-negative organisms

- drug efflux pumps

Partial or complete cross-resistance between cefpodoxime and other cephalosporins and penicillins exists.

Breakpoints

Breakpoint recommendations for cefpodoxime according to the European Committee on Antimicrobial Susceptibly Testing (EUCAST) have been defined (Breakpoint tables for interpretation of MICs and zone diameters, Version 2.0, January 2012):

Cefpodoxime (EUCAST Clinical Breakpoint Table)	MIC breakpoints
	S <	R >
Enterobacteriaceae (uncomplicated UTI only)	1	1
Pseudomonas spp.	-	-
Acinetobacter spp.	-	-
Staphylococcus spp.	Note¹	Note¹
Enterococcus spp.	-	-
Streptococcus groups A,B,C and G	Note²	Note²
Streptococcus pneumoniae	0.25	0.5
Viridans group streptococci	-	-
Haemophilus influenzae	0.25³	0.5
Moraxella catarrhalis	IP	IP
Neisseria gonorrhoeae	IE	IE

Cefpodoxime (EUCAST Clinical Breakpoint Table)	MIC breakpoints
	S <	R >
Neisseria meningitidis	-	-
Gram-positive anaerobes (except Clostridium difficile)	-	-
Gram-negative anaerobes	-	-
Non-species related breakpoints	IE	IE

Note¹: Susceptibility of staphylococci to cephalosporins is inferred from the cefoxitin susceptibility except for ceftazidime, cefixime and ceftibuten, which do not have breakpoints and should not be used for staphylococcal infections.

Note : The beta-lactam susceptibility of beta-haemolytic streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.

- 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.

"-" indicates that susceptibility testing is not recommended as the species is a poor target for therapy with the drug. Isolates may be reported as R without prior testing.

"IE" indicates that there is insufficient evidence that the species in question is a good target for therapy with the drug. An MIC with a comment but without an accompanying S, I or R categorisation may be reported.

IP = In Preparation

Susceptibility

The prevalence of acquired resistance may vary geographically and with 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:

Staphylococcus aureus (methicillin susceptible)

Coagulase-negative staphylococci (methicillin-susceptible)

Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes

Aerobes, Gram negative: Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Proteus mirabilis

Species for which resistance may be a problem Aerobes, Gram positive:

Staphylococcus aureus $

Staphylococcus epidermidis $ +

Staphylococcus haemolyticus $ +

Staphylococcus hominis $ +

Staphylococcus saprophyticus $

Streptococcus pneumoniae (Penicillin-intermediate)

Aerobes, Gram negative Citrobacter freundii$

Enterobacter cloacae$

Escherichia coli&'$

Klebsiella pneumoniae %

Serratia marcescens$

Resistant

Bacteroides fragilis

Clostridium difficile

Enterococcus spp

Listeria monocytogenes

Morganella morganii

Pseudomonas aeruginosa

Streptococcus pneumoniae (Penicillin-resistant)

Other

Chlamydia spp.

Chlamydophila spp.

Legionella pneumophila Mycoplasma spp.

Natural intermediate susceptibility.

% ESBL-producing strains are always resistant

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

Resistance rates < 10% in outpatients + In at least 1 region resistance rates > 50%

5.2 Pharmacokinetic properties

Cefpodoxime proxetil is taken up in the intestine and is hydrolysed to the active metabolite cefpodoxime. When cefpodoxime proxetil is administered orally to fasting subjects as a tablet corresponding to 100 mg of cefpodoxime, 51.1% is absorbed and absorption is increased by food intake. The volume of distribution is 32.3 l and peak levels of cefpodoxime occur 2 to 3 hours after dosing. The maximum plasma concentration is 1.2 mg/l and 2.5 mg/l after doses of 100 mg and 200 mg respectively. Following administration of 100 mg and 200 mg twice daily over 14.5 days, the plasma pharmacokinetic parameters of cefpodoxime remain unchanged.

Serum protein binding of cefpodoxime, 40% principally to albumin. This binding is non-saturable in type.

Concentrations of cefpodoxime in excess of the minimum inhibitory levels (MIC) for common pathogens can be achieved in lung parenchyma, bronchial mucosa, pleural fluid, tonsils, interstitial fluid and prostate tissue.

Studies in healthy volunteers show median concentrations of cefpodoxime in the total ejaculate 6-12 hours following administration of a single 200 mg dose to be above the MIC90 of N. gonorrhoeae.

As the majority of cefpodoxime is eliminated in the urine, the concentration is high. (Concentrations in 0-4, 4-8, 8-12 hour fractions after a single dose exceed MIC90 of common urinary pathogens). Good diffusion of cefpodoxime is also seen into renal tissue, with concentrations above MIC90 of the common urinary pathogens 3-12 hours after an administration of a single 200 mg dose (1.6-3.1 pg/g). Concentrations of cefpodoxime in the medullary and cortical tissues are similar.

The main route of excretion is renal, 80% is excreted unchanged in the urine with an elimination half-life of approximately 2.4 hours.

CHILDREN

In children, studies have shown the maximum plasma concentration occurs approximately 2-4 hours after dosing. A single 5mg/kg dose in 4-12 years olds produced a maximum concentration similar to that in adults given a 200mg dose.

In patients below 2 years receiving repeated doses of 5mg/kg 12 hourly, the average plasma concentrations, 2hrs post dose, are between 2.7mg/1 (1-6 months) and 2.0mg/l (7 months - 2 years).

In patients between 1 month and 12 years receiving repeated doses of 5mg/kg 12 hourly, the residual plasma concentration at steady state are between 0.2 0.3mg/l (1 month - 2 years) and 0.1mg/l (2-12 years).

5.3 Preclinical safety data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Acute Toxicity

The median lethal dose in mice and rats was above 8 g/kg and 4 g/kg bodyweight, respectively. In Fisher rats doses of 1 g/kg body weight and higher influenced stool consistency and weight gain. Single doses of 800 mg/kg body weight were non-toxic in dogs.

Repeat-dose toxicity

Chronic toxicity studies were carried out over 12 months in rats and 6 months in dogs. Maximum daily doses (1000 mg/kg body weight orally in rats and 400 mg/kg orally in dogs) were considerably higher than recommended therapeutic doses (3-8 mg/kg body weight). No mortality was observed in rats receiving 250, 500 or 1000 mg/kg for 12 months. Only at 1000 mg/kg, effects on the GI-tract, softened stools and dilatation of the caecum were observed. Intestinal side effects, which were more pronounced in Fisher rats, are due to the change in intestinal flora caused by the pronounced antibacterial effect of cefpodoxime. Daily administration of 0, 25, 100, and 400 mg/kg body weight to dogs did not reveal mortality. Unchanged cefpodoxime was detected in faeces.

Reproduction toxicity

Embryotoxicity studies in rats and rabbits have not revealed any signs of teratogenic potential. Cefpodoxime had no adverse effects on fertility and peri-/postnatal toxicity studies in rats. Cefpodoxime or its metabolites cross the placenta and are excreted in breast milk in rats. No experience is available on the use of cefpodoxime during pregnancy and lactation in humans.

Mutagenicity

Extensive mutagenicity testing in different testing models was negative.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose,

Guar Galactomannan, Aspartame,

Orange Flavouring, Sodium Benzoate, Sodium Chloride,

Citric Acid Anhydrous, Lemon Flavouring, Sorbitan Trioleate,

Talc,

Yellow Ferric Oxide (E172), Silicon Dioxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

After preparation the suspension can be kept in the refrigerator (2-8°C) for 14 days without any significant loss of activity.

6.4 Special precautions for storage

Do not store above 25°C. Keep the container tightly closed. Store reconstituted suspension between 2°C and 8°C.

6.5 Nature and contents of container

50 ml, 100 ml and 2 x 100 ml brown glass bottle with desiccant stopper.

A 10 ml syringe is inserted in the carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Brown glass bottles with desiccant stopper:

Before preparing the suspension the silica gel desiccant contained in a capsule inside the cap must be removed and disposed of. The suspension is prepared by adding water to the bottle up to the calibrated mark and shaking thoroughly to obtain an evenly dispersed suspension.

7 MARKETING AUTHORISATION HOLDER

Sandoz GMBH Biochemistrasse 10 Kundl A6250

8 MARKETING AUTHORISATION NUMBER(S)

PL 04520/0138

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/10/2010

10 DATE OF REVISION OF THE TEXT

13/10/2010