CEFPODOXIME ARROW 40 mg/5 mL Powder for oral suspension child infant Bottle/100mL

Cefpodoxime..................................................................................................................................................40 mg

In the form of Cefpodoxime proxetil

Per 5 mL of reconstituted suspension

Excipients with known effect: sucrose, aspartame (E951), sodium, sodium benzoate (E211).

They derive from the antibacterial activity and the pharmacokinetic characteristics of cefpodoxime.

In children, they are limited to the treatment of infections due to germs sensitive to cefpodoxime, and in particular:

• acute otitis media,

• tonsillitis documented to be due to beta-haemolytic streptococcus group A,

• sinusitis,

• lower respiratory tract infections.

Official recommendations concerning the appropriate use of antibacterial agents should be taken into account.

The oral suspension presentation is recommended in children. In certain cases, the use of a tablet presentation may be considered within the validated paediatric indications and dosages if the child is able to swallow the tablet.

Dosage

Normorenal child

The average dose is 8 mg/kg/day, not exceeding the adult dose (200 mg/day in tonsillitis and 400 mg/day in other indications), divided into 2 doses at 12 hour intervals.

The duration of treatment for tonsillitis is 5 days.

Renal insufficiency

If creatinine clearance is > 40 mL/min/1,73 m2, refer to the dosage for the normal-renal function subject.

If creatinine clearance is < 40 mL/min/1,73 m2, see the table below:

In case of hemodialysis, a unit dose will be administered after each dialysis session.

Hepatic impairment

It is not necessary to modify the dosage.

Method of administration

Oral use.

The oral suspension is to be administered during a meal.

Before preparing the suspension, the capsule containing the desiccant, located inside the cap, must be removed and discarded.

The powder contained in the bottle is made into a suspension by adding water at the time of use up to the graduation mark.

The bottle must be shaken in order to homogenize the resulting suspension.

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

• In case of known allergy to antibiotics of the cephalosporin group.

Special warnings

• The occurrence of any allergic reaction requires discontinuation of treatment.

• Prescribing cephalosporins requires prior questioning, as allergy to penicillins is cross-reactive with allergy to cephalosporins in 5 to 10 % of cases:

• the use of cephalosporins must be extremely cautious in patients sensitive to penicillin: strict medical monitoring is necessary from the first administration;
•  the use of cephalosporins is strictly contraindicated in subjects with a history of immediate-type allergy to cephalosporins. In case of doubt, the presence of the physician with the patient is essential at the first administration, in order to treat a possible anaphylactic accident;
•  hypersensitivity reactions (anaphylaxis) observed with these two types of beta-lactams can be serious and sometimes fatal.

• The occurrence of an episode of diarrhea may, exceptionally, be symptomatic of pseudomembranous colitis, the diagnosis of which relies on colonoscopy.

• This accident, rare with cephalosporins, requires immediate discontinuation of treatment and initiation of appropriate specific antibiotic therapy (vancomycin). In this case, the administration of products promoting fecal stasis must absolutely be avoided.

• Hematological disorders 

As with other antibiotics of the beta-lactam class, neutropenia and more rarely agranulocytosis may develop during treatment with cefpodoxime, particularly if treatment is long-term. In this case, hematological monitoring should be considered.

• Bullous eruptions 

As with other cephalosporins, cases of bullous eruptions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. If skin and/or mucous membrane involvement occurs, patients must immediately contact their doctor, before continuing treatment.

• Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) of unknown frequency, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported in association with treatment with cefpodoxime.

Patients must be informed of the signs and symptoms and be closely monitored in case of skin reactions.

If signs or symptoms suggestive of these reactions appear, treatment with cefpodoxime must be stopped immediately and an alternative treatment should be considered.

If the patient develops a severe reaction such as SJS, TEN, DRESS or AGEP associated with the use of cefpodoxime, treatment with cefpodoxime must under no circumstances be resumed in this patient.

• Superinfection 

As with other antibiotics, administration of cefpodoxime, particularly if treatment is long-term, may lead to excessive growth of non-susceptible microorganisms. Regular assessments of the patient's condition are essential. If superinfection occurs during treatment, appropriate measures must be taken.

• Encephalopathy 

Beta-lactams, including cefpodoxime, predispose the patient to the risk of encephalopathy (which may include convulsions, confusion, disturbances of consciousness or abnormal movements) and, particularly, in cases of overdose or renal insufficiency.

Precautions for use

• In patients allergic to other beta-lactams, the possibility of cross-allergy must be taken into account.

• In case of severe renal insufficiency, it may be necessary to adjust the daily dose according to creatinine clearance (see sections Dosage and administration and Pharmacokinetics paragraph "Subjects at risk").

• This medicine must not be used in children under 15 days old, in the absence of specific studies.

• As with other broad-spectrum antibiotics, prolonged use of cefpodoxime may lead to selection of non-susceptible organisms, which may necessitate interruption of treatment.

• Interactions with laboratory tests. 

• A positive Coombs test has been described during treatment with cephalosporins.

• A false-positive reaction may occur when testing urine for glucose with reducing substances, but not when using glucose oxidase methods.

Excipients with known effect

This medicine contains sucrose. Patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase/isomaltase deficiency (rare hereditary diseases) must not take this medicine. The medicine may be harmful to teeth if it must be taken over a prolonged period, for example for two weeks or more.

This medicine contains 25 mg of aspartame per 5 mL of reconstituted suspension. Aspartame contains a source of phenylalanine. This may be harmful to people with phenylketonuria (PKU), a rare genetic disease characterised by the accumulation of phenylalanine that cannot be properly eliminated. There is no clinical or non-clinical data on the use of aspartame in children under 12 weeks old.

This medicine contains 3,56 mg of sodium per 5 mL of reconstituted suspension, which is equivalent to 0,18 % of the maximum recommended daily dietary intake of 2 g of sodium for an adult by the WHO.

This medicine contains 10 mg of sodium benzoate per 5 mL of reconstituted suspension. Benzoate salt may increase the risk of jaundice (yellowing of the skin and eyes) in newborns (up to 4 weeks).

Modification of gastric pH

Increase in gastric pH: anti-H2 (ranitidine) and antacids (aluminium hydroxide, sodium bicarbonate) lead to a decrease in bioavailability.

On the other hand, a decrease in gastric pH (pentagastrin) causes an increase in bioavailability.

The clinical consequences remain to be established.

Specific problems with INR imbalance

Numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antibiotics. A marked infectious or inflammatory context, the patient's age and general condition appear to be risk factors.

In these circumstances, it appears difficult to distinguish between the infectious pathology and its treatment in the occurrence of the INR imbalance. However, certain classes of antibiotics are more often implicated: these notably include fluoroquinolones, macrolides, cyclines, cotrimoxazole and certain cephalosporins.

If undesirable effects such as dizziness or encephalopathy (which may include convulsions, confusion, disturbances of consciousness or abnormal movements) occur (see sections Warnings and precautions, Adverse effects, Overdose), the patient must not drive or use machines.

Frequencies were defined using the following criteria: very common (≥ 10 %); common (≥ 1 % and < 10 %); uncommon (≥ 0,1 % and < 1 %); rare (≥ 0,01 % and < 0,1 %); very rare (< 0,01 %), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Uncommon: neutropenia.

Rare: thrombocytosis, leukopenia.

Frequency not known: agranulocytosis, eosinophilia, thrombocytopenia, haemolytic anaemia.

Ear and labyrinth disorders

Common: tinnitus.

Gastrointestinal disorders

Very common: abdominal pain, diarrhoea.

Common: nausea, vomiting.

Uncommon: enterocolitis.

Frequency not known: haematochezia, pseudomembranous colitis, colitis due to Clostridium difficile.

General disorders and administration site conditions

Frequency not known: malaise, asthenia.

Hepatobiliary disorders

Common: increased AST (aspartate aminotransferase), increased ALT (alanine aminotransferase), increased alkaline phosphatase.

Frequency not known: increased blood bilirubin, hepatic injury, cholestatic hepatic injury.

Immune system disorders

Uncommon: anaphylactic reactions, bronchospasm.

Frequency not known: anaphylactic shock, Quincke's oedema.

 Infections and infestations

Frequency not known: superinfection.

Nervous system disorders

Very common: headache.

Common: vertigo.

Frequency not known: paraesthesia, convulsions.

Beta-lactams, including cefpodoxime, predispose the patient to the risk of encephalopathy (which may include convulsions, confusion, impaired consciousness or abnormal movements), particularly in cases of overdose or impaired renal function.

Skin and subcutaneous tissue disorders

Common: rash, pruritus, urticaria.

Frequency not known: purpura, bullous dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders

Rare: slight increase in blood urea and serum creatinine

Frequency not known: renal function impairment has been reported with antibiotics belonging to the same therapeutic class as cefpodoxime, particularly when they are combined with aminoglycosides and/or potent diuretics.

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

Beta-lactams, including cefpodoxime, predispose the patient to the risk of encephalopathy, particularly in cases of overdose or renal insufficiency.

Pharmacotherapeutic class: antibacterials for systemic use, ATC code: J01DD13.

Cefpodoxime proxetil is a semi-synthetic antibiotic of the beta-lactam family, from the group of oral third-generation cephalosporins, a prodrug of cefpodoxime.

After oral administration, cefpodoxime proxetil is absorbed in the intestine and rapidly hydrolysed by non-specific esterases into cefpodoxime, a bactericidal antibiotic.

The mechanism of action of cefpodoxime is based on the inhibition of bacterial cell wall synthesis. Cefpodoxime is stable against many beta-lactamases.

Susceptibility testing breakpoints

The criteria for interpreting minimum inhibitory concentrations (MICs) for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for cefpodoxime and are listed below:

https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

The prevalence of acquired resistance can vary according to geography and time for certain species. It is therefore useful to have information on local resistance prevalence, especially for the treatment of severe infections. These data can only provide guidance on the probabilities of the susceptibility of a bacterial strain to this antibiotic.

When the variability in the prevalence of resistance in France is known for a bacterial species, it is indicated in the table below:

*The frequency of methicillin resistance is approximately 30 to 50 % of all staphylococci and is found mainly in hospital settings.

IN ADULTS

Absorption

The absorption of cefpodoxime proxetil administered orally to fasting subjects, in the form of a tablet corresponding to 100 mg of cefpodoxime, is 40 to 50 %.

This is increased by food intake, so it is recommended that the product be administered with meals.

Distribution

• Plasma concentrations:

• after oral administration of a single dose of 100 mg, the maximum plasma concentrations of cefpodoxime (Cmax) are 1 mg/L to 1,2 mg/L. After administration of a dose of 200 mg, the maximum plasma concentrations are 2,2 to 2,5 mg/L. In both cases (100 or 200 mg), they are reached (Tmax) at 2 to 3 hours.
• the residual concentrations at 12 hours are respectively 0,08 mg/L and 0,18 mg/L after administration of 100 mg and 200 mg;
• after administration for 14,5 days of 100 to 200 mg, 2 times per day, the plasma pharmacokinetic parameters of cefpodoxime are not modified, reflecting the absence of accumulation of the active substance.

• The volume of distribution of cefpodoxime is 30-35 L in healthy young subjects (= 0,43 L/kg).

• Binding to plasma proteins.

The binding rate of cefpodoxime is of the order of 40% and occurs mainly on albumin. This binding is of the non-saturable type.

• Humoral and tissue diffusion:

• cefpodoxime has good diffusion into the lung parenchyma, bronchial mucosa, pleural fluid, tonsils and interstitial fluid;
• 4 to 7 hours after a single intake of 100 mg, tonsillar concentrations are 0,24 to 0,1 µg/g (20 to 25% of plasma concentrations);
• after a single intake of 200 mg of cefpodoxime, concentrations in interstitial fluid are 1,5 to 2,0 mg/L (80% of plasma concentrations);
• 3 to 12 hours after a single intake of 200 mg of cefpodoxime, concentrations in the lung are 0,6 to 0,2 µg/g; in the pleura, they are 0,6 to 0,8 mg/L;
• in the bronchial mucosa, between 1 and 4 hours after administration of 200 mg, cefpodoxime concentrations are around 1 µg/g (40 to 45% of plasma concentrations);
• the measured concentrations are greater than the MICs of susceptible microorganisms.

Biotransformation and elimination

• After absorption, the main metabolite is cefpodoxime, resulting from the hydrolysis of cefpodoxime proxetil.

• Cefpodoxime is very little metabolised.

• After absorption of cefpodoxime proxetil, 80% of the released cefpodoxime is eliminated unchanged in the urine.

•  The elimination half-life of cefpodoxime is on average 2,4 hours.

At-risk subjects

• The pharmacokinetic parameters of cefpodoxime are very slightly modified in elderly subjects with normal renal function.

However, the small increase in maximum serum concentrations and in elimination half-life does not justify any dose reduction in this population, except in subjects whose renal clearance is less than 40 mL/min.

• In case of renal impairment, corresponding to a creatinine clearance less than 40 mL/min,

the increase in plasma elimination half-life and maximum plasma concentrations leads to halving the dose and administering it as a single daily intake.

• In case of hepatic impairment, the small kinetic changes observed do not justify a specific dose adjustment.

IN CHILDREN

After oral administration of a single dose of 5 mg/kg (maximum 200 mg) expressed as cefpodoxime, to subjects aged 4 to 12 years, the maximum plasma concentrations of cefpodoxime (Cmax) are on average 2,6 mg/L. They are reached at 2 to 4 hours.

In patients under 2 years of age with repeated administration of 5 mg/kg every 12 hours, the mean plasma concentrations, 2 hours after administration, are between 2,7 mg/L (1 month - 6 months) and 2,0 mg/L (7 months to -2 years).

In patients aged 1 month to 12 years after repeated administration of 5 mg/kg every 12 hours, the residual plasma concentrations of cefpodoxime (C12h) at steady state are between 0,2 to 0,3 mg/L (1 month - 2 years) and 0,1 mg/L (2 years - 12 years).

3 years.

After reconstitution : 14 days.

Store at a temperature not exceeding 25°C.

After reconstitution: store in the refrigerator (between 2°C and 8°C).

No special requirements.