Document: spc-doc_PL 04569-0981 change

• spc-doc_PL 04520-0136
• spc-doc_PL 04569-0981

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Cefpodoxime 100mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains cefpodoxime proxetil corresponding to 100 mg cefpodoxime. Excipient with known effect:

Each 100 mg tablet contains 24 mg lactose monohydrate For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Round, white to yellowish tablets with a diameter of approx. 9 mm.

4.1 Therapeutic indications

Cefpodoxime is indicated for the treatment of the following infections when caused by susceptible organisms (see section 5.1).

•    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

Adults and adolescents with normal renal function:

Acute bacterial sinusitis: 200mg twice daily.

Tonsillitis and pharyngitis: 100mg twice daily

Acute, exacerbation of chronic bronchitis and bacterial pneumonia: 200 mg twice daily

Elderly

It is not necessary to modify the dose in elderly patients with normal renal function.

Paediatric population

Cefpodoxime Powder for oral Suspension may be available to treat infants (over 28 days (4 weeks) old) and children. Please refer to the separate Summary of Product Characteristics for details.

Renal Impairment

The dose of cefpodoxime does not require modification if creatinine clearance exceeds 40ml/min/1.73 m². Below this value, pharmacokinetic studies indicate an increase in plasma elimination half-life. Therefore, the dose should be adjusted appropriately.

CREATININE CLEARANCE (ML/MIN/1.73 m2)
39 - 10	Unit dose' administered as a single dose every 24 hours.
<10	Unit dose' administered as a single dose every 48 hours.
Haemodialysis Patients	Unit dose' administered after each dialysis session.

NOTE: 'the unit dose is either 100mg or 200mg, depending on the type of infection as stated above.

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.

The tablets should be taken with food for optimum absorption. The tablets should be swallowed whole with sufficient liquid (e.g. 1 glass of water).

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.

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/1.73 m² 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.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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	Erythema 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

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.

Antibacterial spectrum

Commonly Susceptible species_

Aerobic Gram positive organisms:_

Staphylococcus aureus (Methicillin-susceptible)

Streptococcus pyogenes_

Aerobic Gram negative organisms:_

Haemophilus influenzae_

Moraxella catarrhalis_

Proteus mirabilis^%_

Species for which acquired resistance may be

a problem_

Aerobic Gram positive organisms_

Streptococcus pneumoniae_

Aerobic Gram negative organisms_

Citrobacter ^ freundi_

Enterobacter cloacae^$

Escherichia coli%_

Klebsiella pneumoniae°^/°_

Serratia marcescens$

Inherently resistant organisms_

Aerobic Gram positive organisms_

Enterococcus spp._

Staphylococcus aureus (methicillin resistant)

Aerobic Gram negative organisms_

Morganella morganii_

Pseudomonas aeruginosa._

Others_

Chlamydia spp._

Chlamydophila spp._

Legionella pneumophila_

Mycoplasma spp._

^$ 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.

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) *administered as cefpodoxime proxetil

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, C_max 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 C_max 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 C_max 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 metabolized, 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_J/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.

Mutagenicity

Extensive mutagenicity testing in different testing models was negative.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Carboxymethylcellulose calcium, Lactose monohydrate, Crospovidone, Hydroxypropyl-cellulose, Magnesium stearate,

Sodium lauril sulfate.

Coating:

Hypromellose,

Talc,

Titanium dioxide (E171).

6.2    Incompatabilities

Not applicable.

6.3    Shelf life

Alu-Alu blister:    3 years

Alu-PVC/PVDC blister:    2 years

6.4    Special precautions for storage

Alu-PVC/PVDC blister: Do not store above 25°C. Store in the original package Alu-Alu blister: Store in the original package.

6.5    Nature and contents of container

Nature: Alu-Alu or Alu-PVC/PVDC blister packs Contents: 100 mg: 10, 12, 20, 30 tablets Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements

1

Susceptibility of staphylococci to cephalosporins is inferred from the cefoxitin susceptibility

2

except for ceftazidime, cefixime and ceftibuten, which do not have breakpoints and should

3

not be used for staphylococcal infections. Some methicillin-resistant S. aureus are susceptible to ceftaroline and ceftobiprole.