Document: spc-doc_PL 04569-0980 change

• spc-doc_PL 04520-0138
• spc-doc_PL 04569-0980

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Cefpodoxime 40mg/5ml Powder for Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients with known effect:

5 ml of reconstituted suspension contain 1848.58 mg sucrose.

Each 5 ml of reconstituted solution contains 25 mg of 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.

4.1 Therapeutic indications

Cefpodoxime is indicated for the treatment of the following infections when caused by susceptible organisms (see section 5.1) in children up to 11 years.

-    Acute otitis media

-    Acute bacterial sinusitis

-    Tonsillitis and pharyngitis

-    Acute exacerbation of chronic bronchitis

-    Bacterial pneumonia

(See section 4.4)

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

4.2 Posology and method of administration

Posology

Paediatric population (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 28 days (4 weeks) old as there is no experience in this age group.

Renal Impairment

Cefpodoxime is contraindicated in infants between 4 weeks and 3 months with renal impairment (see section 4.3).

For other children, the dose of cefpodoxime does not require modification if creatinine clearance exceeds 40ml/min/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/1.73m2)
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)

When treating infections caused by the bacterial species Streptococcus pyogenes, a duration of treatment of at least 10 days is indicated in order to prevent late complications such as rheumatic fever or a severe kidney disease, glomerulonephritis.

Method of administration For oral administration.

Doses should be taken during meals for optimal absorption.

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

4.3 Contraindications

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

Previous history of immediate and / or severe hypersensitivity reactions (anaphylaxis) to penicillin or other beta-lactam antibiotic.

Newborn infants up to the age of 28 days (4 weeks).

Infants between 4 weeks and 3 months with renal impairment (see section 4.2), as there is no experience in this population.

Phenylketonuria since the product contains aspartame.

4.4 Special warnings and precautions for use

As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefpodoxime must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of severe

hypersensitivity reactions to cefpodoxime, to other cephalosporins or to any other type of beta-lactam

agent. Cefpodoxime may be given with caution to patients with a history of non-severe hypersensitivity reactions (for contraindications related to hypersensitivity, see section 4.3).

Cefpodoxime should also be used with particular caution in patients with a high likelihood of allergic reactions of another type (e.g. hayfever or bronchial asthma), as in these cases, the risk of severe hypersensitivity reactions is increased.

In cases of severe renal insufficiency it may be necessary to reduce the dose dependent on the creatinine clearance. At a creatinine clearance of less than 40 ml/min/1.73m² and in haemodialysis patients, an increase in the dose interval is necessary (see section 4.2).

Cefpodoxime should always be used with caution in patients with a history of gastrointestinal disease, particularly colitis.

In the case of severe gastrointestinal disorders with vomiting and diarrhoea, the administration of cefpodoxime is not appropriate, as sufficient absorption from the gastrointestinal tract is not achieved.

Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including cefpodoxime, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of cefpodoxime (see section 4.8). Discontinuation of therapy with cefpodoxime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

The use of cefpodoxime can lead to vomiting and diarrhoea (see section 4.8). In this case, the efficacy of this and/or other medicinal products which have been taken (such as oral contraceptives) may be impaired.

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.

During treatment with cephalosporins, non-enzymatic methods to determine the level of glucose in the urine may give false positive results (see section 4.5).

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

As with other antibiotics, the long term or repeated use of cefpodoxime may lead to a superinfection and result in the overgrowth of non-susceptible organisms (e.g. oral thrush, vaginitis).

Erythema multiforme, Stevens-Johnson syndrome, Lyell’s syndrome: the medicinal product should be discontinued if symptoms of this type occur.

The product should not be used in infants less than 28 days (4 weeks) old as no clinical trial data in this age group yet exists.

This medicine contains 1.8 g of sucrose per 5 ml. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains aspartame and is therefore unsuitable for patients with phenylketonuria (see section 4.3).

4.5 Interaction with other medicinal products and other forms of interaction

In the case of high dose treatment with parenterally administered medicinal products With the administration of cephalosporins and concomitantly administered strong saluretics (e.g. furosemide) or potentially nephrotoxic preparations (e.g. aminoglycoside antibiotics), it has not been possible to rule out an impairment of renal function. Pharmacological data and clinical experience show, however, that this is unlikely with cefpodoxime, which is for oral use, at the recommended dose.

Studies have shown that bioavailability is decreased by approximately 30% when cefpodoxime is administered with drugs which neutralise gastric pH or inhibit acid secretions in patients with empty stomachs.

The studies carried out on this to date show the following results:

Antacids:

Aluminium hydroxide -27%

Sodium bicarbonate    -32%

H2 receptor blocker:

Ranitidine    -29%

As a result, these preparations should be taken 2 to 3 hours after cefpodoxime administration.

Antibiotics with a bacteriostatic effect

Where possible, cefpodoxime should not be combined with antibiotics with a bacteriostatic effect (such as chloramphenicol, erythromycin, sulfonamide or tetracycline), as the effect of cefpodoxime may be decreased.

Probenecid reduces the excretion of cephalosporins.

Cephalosporins potentially enhance the anticoagulant effect of coumarins. It is recommended that the INR should be monitored frequently during and shortly after co-administration of cefpodoxime with an oral anti-coagulant agent

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

Pregnancy

For cefpodoxime 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). Due to the lack of clinical experience, cefpodoxime should only be used, in the first three months of pregnancy in particular, after a careful assessment of the risks and benefits.

Breast-feeding

Cefpodoxime is excreted in human milk in small quantities. Breast-fed infants can therefore experience changes to the intestinal flora with diarrhoea and yeast infections, so breastfeeding may need to be stopped. The possibility of sensitisation must also be taken into account. Cefpodoxime should therefore only be used during breast-feeding after a careful assessment of the risks and benefits.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

In this section the frequencies of 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).

Adverse Drug Reactions by System Organ Class and Frequency
Infections and infestations
Common	Superinfections with non-sensitive microorganisms, e.g. yeast fungus, Candida (see section 4.4)
Blood and lymphatic system disorders
Uncommon	Thrombocytosis, this change is mostly reversible once the treatment has ended.
Rare	Haemolytic anaemia, eosinophilia, agranulocytosis, lymphocytosis, anaemia, leucopenia, neutropenia, leukocytosis, thrombocytopenia
Immune system disorders
Rare	Hypersensitivities of all severities, e.g. angioedema, anaphylactic reactions, bronchospasm through to life threatening shock (see section 4.4)
Metabolism and nutrition disorders
Common	Decreased appetite
Nervous system disorders

Uncommon	Headaches, paraesthesias, dizziness
Ear and labyrinth disorders
Uncommon	Tinnitus
Gastrointestinal disorders
Common	Abdominal distension, nausea, vomiting, abdominal pain, flatulence, diarrhoea.
Rare	Bloody diarrhoea can occur as a symptom of enterocolitis. The possibility of pseudomembranous enterocolitis should be considered if severe or persistent diarrhoea occurs during or after treatment (see section 4.4), acute pancreatitis
Hepatobiliary disorders
Uncommon	Increases in liver enzymes (transaminases,alkaline phosphatase) and/or bilirubin as a symptom of (for example) cholestatic liver injury.
Rare	Acute hepatitis
Skin and subcutaneous tissue disorders
Uncommon	Skin changes with and without itching (erythema, exanthema, urticaria, purpura),mucocutaneous skin reactions, pruritis
Rare	Eythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome
Renal and urinary disorders
Rare	Slight increases in blood urea and creatinine, acute renal insufficiency
General disorders and administration site conditions
Uncommon:	Weakness such as asthenia, tiredness and malaise

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 www.mhra.gov.uk/yellowcard.

4.9 Overdose

There is no knowledge of significant overdoses in humans.

In rare cases, overdoses up to a daily dose of 1,000 mg of cefpodoxime have been reported. The undesirable effects observed were the same as those at the recommended dose. In patients with renal insufficiency, encephalopathy may occur. The encephalopathy is usually reversible once cefpodoxime plasma levels have fallen.

In the event of overdose with cefpodoxime, supportive and symptomatic therapy is indicated. Cefpodoxime can be broken down by dialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other beta -lactam antibacterials, third generation cephalosporins, ATC code: J01DD13

Mechanism of action

Like other beta-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.

Pharmacokinetic/pharmacodynamic relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftazidime for individual target species (i.e. %T>MIC).

Mechanisms of resistance

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

•    Deactivation through beta-lactamases. Cefpodoxime may be efficiently hydrolysed by certain beta-lactamases of the extended-spectrum beta-lactamases (ESBLs) which occur for example, in strains of Escherichia coli or Klebsiella pneumoniae and by the chromosomally-encoded (AmpC) enzyme that may be induced or stably derepressed in certain aerobic gram-negative bacterial species, e.g. Enterobacter cloacae. In the case of infections by bacteria with inducible AmpC-beta-lactamase and in-vitro sensitivity to cefpodoxime, there is a risk that during treatment mutants with constitutive (depressed) AmpC beta-lactamase formation will be selected.

•    Reduced affinity of penicillin-binding proteins (PBPs) for cefpodoxime: the acquired resistance in pneumococci and other streptococci is based on modifications of existing PBPs as a result of a mutation. For resistance in methicillin (oxacillin) resistant staphylococci, however, the formation of an additional PBP with decreased affinity to cefpodoxime is responsible.

•    Insufficient penetration of cefpodoxime through external cell wall in Gram-negative bacteria can lead to the PBPs not being sufficiently inhibited.

•    Cefpodoxime can be actively transported out of the cell by way of drug efflux pumps

Break points:

European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented below. EUCAST clinical MIC breakpoints for cefpodoxime (2015-01-01, v.5.0)

Organism	Susceptible (S) (mg/l)	Resistant (R) (mg/l)
Enterobacteriaceae (uncomplicated UTI only)	< 1	>1
Staphylococcus spp.	Note1	Note1
Streptococcus groups A, B, C and G	Note2	Note2
Streptococcus pneumoniae	< 0.25	>0.5
Haemophilus influenzae	< 0.25 Note3	>0.5
Moraxella catarrhalis	IP	IP
Neisseria gonorrhoeae
Non-species related breakpoint	IE	IE

1    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. Some methicillin-resistant S. aureus are susceptible to ceftaroline and ceftobiprole.

2    The susceptibility of streptococcus groups A, B, C and G is inferred from the benzylpenicillin susceptibility.

3    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 IE: Insufficient evidence 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.

$ natural intermediate susceptibility +Resistance rates >50% in at least 1 region % ESBL producing species are always resistant

5.2 Pharmacokinetic properties

Cefpodoxime proxetil is a prodrug of cefpodoxime.

Absorption

Following oral administration, cefpodoxime proxetil is absorbed in the gastrointestinal tract and rapidly hydrolysed to the active metabolite cefpodoxime in the intestinal mucosa.

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, therefore cefpodoxime proxetil should be taken with a meal.

Children

Following the oral administration of a single dose of 5 mg of cefpodoxime*/kg of body weight (maximum 200 mg*) to children between the ages of 4 and 12, average maximum plasma levels (C_max) of 2.6 mg /L are achieved after 2-4 hours (T_max), The average plasma concentrations 8 and 12 hours after administration were 0.39 and 0.08 mg/L.

*administered as cefpodoxime proxetil

Single administration in adults

Following oral administration of 100 mg cefpodoxime*, average maximum plasma levels (C_max) of 1-1.2 mg/L were achieved; after a single administration of 200 mg of cefpodoxime*, C_max was 2.2-2.5 mg/L. In both cases (100mg/200 mg), the C_max was reached after 2-3 hours

(Tmax).

Multiple administration in adults

In the case of multiple administration of 100 and 200 mg of cefpodoxime* at intervals of 12 hours for a period of 14.5 days, the pharmacokinetic parameters did not show any change, therefore, no accumulation occurred.

Elderly patients

In patients who are 70 years old or above, the steady sate was reached following the repeated administration of 200 mg of cefpodoxime* at 12-hour intervals for a period of 6 to 10 days. In the steady state, Cmax is an average of 3.05 mg/L, and T_max is 2.7 hours.

Patients with liver cirrhosis

In cirrhosis patients with or without ascites, the Cmax following the single administration of 200 mg of cefpodoxime* was an average of 1.67 mg/L, the plasma levels are equivalent to those of a healthy subject 12 hours after administration.

Patients with chronic renal insufficiency

In patients with chronic renal insufficiency, the plasma levels increase as the severity of the disease increases. At a creatinine clearance of less than 40 mL/min/1.73m², (10-40 mL/min), the average C_max after a dose of 200 mg of cefpodoxime* is twice as high as in healthy subjects; the T_max is approximately 4 hours.

Haemodialysis patients

In patients with a creatinine clearance of less than 10 mL/min/1.73m², the average Cmax is 1.5 times higher than in healthy subjects; the T_max is approximately 6 hours.

Cefpodoxime can be broken down by dialysis and therefore has to be administered outside of the dialysis periods.

Distribution

The volume of distribution is 32.3L in young test subjects (=0.43 L/kg).

Serum protein binding of cefpodoxime, is 40% principally to albumin. This binding is nonsaturable 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, kidneys, 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.

Biotransformation

Following absorption, the main metabolite, cefpodoxime, is produced by the hydrolysis of cefpodoxime proxetil.

Cefpodoxime is barely metabolised, following the absorption of cefpodoxime proxetil. Elimination

The main route of excretion is renal, 80% is excreted unchanged in the urine with an elimination half-life of approximately 2.4 hours. The total clearance of cefpodoxime is 9.98L/h; the average renal clearance is 7 L/h.

Elderly patients

In patients over the age of 70 the elimination half-life (T_1/2) increases to an average of 3.6 hours. In patients with chronic renal insufficiency and a creatinine clearance of less than 40 mL/min/1.73m², T_1/2 is over 6 hours (an average of 7.7 hours in the case of a creatinine clearance between 10 and 40 mL/min/1.73m²).

5.3 Preclinical safety data

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,

Iron oxide yellow (E172),

Silicon dioxide.

6.2    Incompatabilities

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.

For storage conditions after reconstitution of the medicinal product, see section 6.3

6.5 Nature and contents of container 50 ml, 100 ml and 2 x 100 ml amber 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 Amber 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

Generics [UK] Limited Station Close Potters Bar Herts.

EN6 1TL

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0980

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/10/2010

10    DATE OF REVISION OF THE TEXT

03/03/2016