ORELOX 40 mg/5 ml Oral Suspension Granules for Children and Infants Bottle/100ml

Granules for oral suspension.

Cefpodoxime proxetil..................................................................................................................................6,261 g

Quantity corresponding to cefpodoxime...................................................................................................4,800 g

For 100 g of granules.

8,35 g of granules correspond to 50 ml of reconstituted suspension, i.e. 100 doses-kg.

16,7 g of granules correspond to 100 ml of reconstituted suspension, i.e. 200 doses-kg.

Excipients with known effect (see sections Contraindications and Warnings and precautions):

• lactose (2,9 mg/ml),

• sucrose (120,27 mg/ml),

• sodium (1,37 mg/ml),

• aspartame (source of phenylalanine) (E 951) 4 mg/ml,

• sorbitol (E 420) 0,136 mg/ml

Excipients:

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

Dosage

Normal renal function children

The average dosage 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 dose per dose is indicated, according to the child's weight, on the plunger of the oral syringe graduated in kg of body weight (graduations from 5 to 25 kg). The dose per intake can therefore be read directly. Thus, the indicated weight corresponds to the dose for one administration. The dose to be administered for one intake is therefore obtained by pulling the plunger to the graduation corresponding to the child's weight. Two doses per day are required. For example, the graduation 12 kg corresponds to the dose to be administered per intake for a child weighing 12 kg, and this twice a day.

The duration of treatment for tonsillitis is 5 days.

Renal insufficiency

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

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

Creatinine clearance (ml/min/1.73 m2)	Doses
10 - 39	One unit dose every 24 hours
< 10	One unit dose every 48 hours

In case of haemodialysis, one 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 granules contained in the bottle are suspended by adding water at the time of use up to the graduation mark. The bottle must be shaken in order to homogenise the resulting suspension.

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

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

• Due to the presence of aspartame, this medicine is contraindicated in cases of phenylketonuria.

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 formally 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 severe 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.

• Related to the presence of excipients with known effect:

• Lactose: this medicine contains lactose. Its use is not recommended in patients with galactose intolerance, lactase deficiency or glucose or galactose malabsorption syndrome (rare hereditary diseases).
• Sucrose: this medicine contains sucrose. Its use is not recommended in patients with fructose intolerance, glucose and galactose malabsorption syndrome or sucrase/isomaltase deficiency.
• Sodium: this medicine contains 68,5 mg of sodium per vial of 50 ml of reconstituted suspension (equivalent to 100 doses-kg) and 137 mg of sodium per vial of 100 ml of reconstituted suspension (equivalent to 200 doses-kg). For information, this corresponds respectively to 3,4 % and 6,9 % of the maximum recommended daily dietary intake of 2 g of sodium for an adult set by the WHO. The presence of sodium should be taken into account from a sodium dose per intake of 23 mg (1 mmol), i.e. from an intake of 33 doses-kg (corresponding to 16,5 ml of reconstituted suspension). This should be considered, particularly in people following a strict low-sodium diet.
• Aspartame: this medicine contains 4 mg of aspartame per mL of solution. Aspartame is a source of phenylalanine and may be harmful to people with phenylketonuria (PKU) (see section Contraindications). There is no clinical or non-clinical data on the use of aspartame in children under 12 weeks of age.
• Sorbitol: this medicine contains 0,136 mg of sorbitol per ml of reconstituted suspension, equivalent to 0,068 mg of sorbitol per dose-kg. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The sorbitol content of oral medicines may affect the bioavailability of other oral medicines administered concomitantly.

• 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, Lyell syndrome) have been reported. If skin and/or mucous membrane involvement occurs, patients must immediately contact their physician, before continuing treatment.

• 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, impaired consciousness or abnormal movements) and, particularly, in cases of overdose or renal insufficiency.

• Severe cutaneous adverse reactions (SCARs)

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

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 occur, 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 not be restarted in this patient at any time.

 

Precautions for use

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

• In cases of severe renal impairment, it may be necessary to adjust the daily dose according to the creatinine clearance (see section Dosage and administration and Pharmacokinetics section "At-risk subjects").

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

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

• Interactions with laboratory tests

• A positive Coombs test has been reported during treatment with cephalosporins.
• A falsely positive reaction may occur when testing for glucose in urine with reducing substances, but not when glucose oxidase methods are used.

Modification of gastric pH

Increased 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. Marked infectious or inflammatory conditions, age and general condition of the patient appear to be risk factors. In these circumstances, it appears difficult to distinguish between the infectious disease and its treatment in the occurrence of INR imbalance. However, certain classes of antibiotics are more often implicated: these include fluoroquinolones, macrolides, cyclines, cotrimoxazole and certain cephalosporins.

In case of adverse effects such as dizziness or encephalopathy (which may include convulsions, confusion, impaired consciousness or abnormal movements) (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 disorder, cholestatic hepatic disorder.

Immune system disorders

Uncommon: anaphylactic reactions, bronchospasm.

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

Infections and infestations

Frequency not known: superinfection.

Nervous system disorders

Very common: headache.

Common: dizziness.

Frequency not known: paraesthesia, convulsions.

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 case of overdose or impairment of renal function.

Skin and subcutaneous tissue disorders

Common: rash, pruritus, urticaria.

Frequency not determined: purpura, bullous dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), 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 determined: impairment of renal function 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 marketing 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 the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/

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

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

(Cephalosporins of 3th generation)

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 inhibition of bacterial cell wall synthesis. Cefpodoxime is stable against many beta-lactamases

ANTIBACTERIAL ACTIVITY SPECTRUM

Critical concentrations separate susceptible strains from strains of intermediate susceptibility, and the latter from resistant ones:

S ≤ 1 mg/L and R > 2 mg/L

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.

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

Categories	Frequency of acquired resistance in France (> 10 %) (extreme values)
SUSCEPTIBLE SPECIES
Gram-positive aerobes
Corynebacterium diphtheriae
Streptococcus
Streptococcus pneumoniae	20 - 60 %
Gram-negative aerobes
Branhamella catarrhalis
Citrobacter koseri
Escherichia coli
Haemophilus influenzae
Klebsiella	0 - 30 %
Neisseria gonorrhoeae
Pasteurella
Proteus mirabilis
Proteus vulgaris	29 - 38 %
Providencia
Anaerobes
Fusobacterium	10 - 20 %
Prevotella	30 - 70 %
Propionibacterium acnes
MODERATELY SUSCEPTIBLE SPECIES
(in vitro intermediate susceptibility)
Gram-positive aerobes
Staphylococcus methicillin-S

 

Categories
RESISTANT SPECIES
Gram-positive aerobes
Enterococci
Listeria monocytogenes
Methicillin-R Staphylococcus *
Gram-negative aerobes
Acinetobacter
Citrobacter freundii
Enterobacter
Morganella morganii
Pseudomonas
Serratia
Anaerobes
Bacteroides fragilis
Clostridium
Peptostreptococcus

* 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 0,08 mg/l and 0,18 mg/l, respectively, after administration of 100 mg and 200 mg.
• After administration for 14,5 days of 100 to 200 mg, 2 times daily, the plasma pharmacokinetic parameters of cefpodoxime are not modified, reflecting the absence of accumulation of the active ingredient.

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

• Binding to plasma proteins.

The protein 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 lung parenchyma, bronchial mucosa, pleural fluid, tonsils and interstitial fluid.
• 4 to 7 hours after a single dose of 100 mg, tonsil concentrations are 0,24 to 0,1 microgram/g (20 to 25 % of plasma concentrations).
• After a single dose of 200 mg of cefpodoxime, concentrations in the interstitial fluid are 1,5 to 2,0 mg/l (80 % of plasma concentrations).
• 3 to 12 hours after a single dose of 200 mg of cefpodoxime, concentrations in the lung are 0,6 to 0,2 microgram/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 microgram/g (40 to 45 % of plasma concentrations).
• The measured concentrations are higher 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 mean elimination half-life of cefpodoxime is 2,4 hours.

At-risk subjects

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

However, the slight increase in maximum serum concentrations and 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 cases of renal impairment, corresponding to a creatinine clearance below 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 (200 mg maximum) expressed as cefpodoxime, to subjects aged 4 to 12 years, the mean maximum plasma concentrations of cefpodoxime (Cmax) are 2,6 mg/l on average. They are reached in 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, range from 2,7 mg/l (1 month - 6 months) to 2,0 mg/l (7 months - 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 range from 0,2 to 0,3 mg/l (1 month - 2 years) and 0,1 mg/l (2 years - 12 years).

2 years.

To be stored at a temperature below 25 °C.

After first opening, the shelf life of the reconstituted suspension is 10 days between 2 °C and 8 °C.

List I

Marketing authorisation (AMM)

CIP 3400933604080 (Fl/100ml).

Price:

6,14 euros (Fl/100ml).

Social Security reimbursement at 65%.
Collection.