B.d Rox

Treatment of following infections caused by B.d Roxil-susceptible organisms , when an oral therapy is indicated:

- Streptococcal pharyngitis and tonsillitis

- Bronchopneumonia, bacterial pneumonia

- Uncomplicated urinary tract infections: pyelonephritis, cystitis

- Skin and soft tissue infections: abscesses, furunculosis, impetigo, erysipelas, pyoderma, lymphadenitis

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

Posology

The dosage depends on the susceptibility of the pathogens, the severity of the disease and on the clinical status of the patient (renal and hepatic function).

Children may benefit of increased posology up to 100 mg/kg/day.

Depending on the severity of the infection, adults may require increased posology. The dosage maximum is 4 g per day.Chronic urinary tract infection may require a prolonged and intensive treatment with continued testing of susceptibility and clinical monitoring.

B.d Roxil 500 mg capsules is not recommended for infants and children under 6 years. For younger children and children with a body weight < 40 kg, liquid oral forms (B.d Roxil 250 mg/ 5 ml or 500 mg/ 5 ml suspension) are available.

- Renal impairment:

The dosage should be adjusted according to creatinine clearance rates to prevent accumulation of B.d Roxil. In patients with creatinine clearance of 50 ml/min or less, the following reduced dosage schedule is recommended as a guideline for adults:

- Children (< 40 kg) with renal impairment:

B.d Roxil is not indicated in children suffering from renal insufficiency and children requiring haemodialysis.

- Dosage for haemodialysis patients:

Haemodialysis eliminates 63% of 1000 mg of cephalosporin after 6 to 8 hours of haemodialysis. Elimination half-time of cephalosporin is about 3 hours during dialysis.

Patients with haemodialysis receive one additional dose of 500 mg - 1000 mg at the end of the haemodialysis.

Hepatic impairment:

No adjustment of posology is necessary.

- Elderly:

As B.d Roxil is excreted by renal route, the dosage should be adjusted if necessary as described under impaired renal function.

Mode of administration

Bioavailability is not affected by food and B.d Roxil may be taken with meals or on an empty stomach. In case of gastro-intestinal disturbances, it may be administered with food.

The capsules are taken unchewed with a liberal quantity of fluid.

Duration of therapy

Treatment should be applied for 2 to 3 further days after regression of the acute clinical symptoms or evidence of bacterial eradication has been obtained. In infections caused by Streptococcus pyogenes up to 10 days treatment may be considered.

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- History of severe reactions to penicillins or to any other beta-lactam drugs.

- B.d Roxil does not penetrate in the CSF and is not indicated for the treatment of meningitis.

- Penicillin is the first drug of choice for the treatment of the Streptococcus pyogenes and for the prevention of rheumatic fever. Data for B.d Roxil are not sufficiently substantial for prophylaxis therapy.

- Special caution should be exercised in patients with history of severe allergies or asthma.

- In patients with a history of non severe hypersensitity to penicillins, or other non-cephalosporin beta -lactam drugs, B.d Roxil should be used with special caution as cross allergies occur (incidence 5-10%).

- Renal impairment. Caution is necessary in patients with renal impairment; the dosage must be adjusted according to the grade of renal impairment.

- History of gastro-intestinal disturbances. B.d Roxil should be used with caution in patients with a history of gastro-intestinal disturbances, particularly colitis.

- The occurrence of diarrhoea may impair the resorption of other medicaments and therefore lead to an impairment of their efficacy.

- Allergic reactions. Treatment must be discontinued at once if allergic reactions occur (urticaria, exanthema, pruritus, fall of blood pressure and increased heart rate, respiratory disturbances, collapse, etc.) and suitable countermeasures should be taken (sympathomimetics, corticosteroids and/or antihistaminics).

- Prolonged use. Particularly on prolonged use frequent checks on the blood count and regular hepatic and renal function tests are advisable. Superinfections with fungi (e.g. candida) can occur on prolonged treatment with B.d Roxil.

- In case of severe and persistent diarrhoea, an antibiotic-associated pseudomembranous colitis should be considered. In that case B.d Roxil must be discontinued immediately and a suitable therapy should be started (e.g. oral vancomycin, 250 mg q.i.d.). Antiperistaltics are contraindicated.

- Severe life-threatening infections or those which require higher posology or repetitive administrations per day may benefit of parenteral cephalosporins.

- The result of the Coombs' test can be transiently positive during or after treatment with B.d Roxil. This also applies to Coombs' tests carried out in newborns whose mothers received treatment with cephalosporins before delivery.

- Forced diuresis leads to a decrease of B.d Roxil blood levels.

- Urinary sugar should be determined enzymatically (e.g. with test strips) during treatment with B.d Roxil since reduction tests can furnish falsely elevated values.

B.d Roxil may cause headache, dizziness, nervousness, sleeplessness and fatigue, therefore the ability to drive and use machines may be influenced.

The adverse events are ranked under headings of frequency, using the following convention:

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 form the available data).

Adverse drug reactions occur in about 6% to 7%* of treated patients.

*incidence of suspected adverse reactions in an observational post-marketing study in 904 patients.

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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

No clinical reports are as yet available on B.d Roxil in this respect. However in view of experience gained with other cephalosporins the following symptoms are possible: nausea, hallucinations, hyperreflexia, extrapyramidal symptoms, clouded consciousness, or even coma and renal functional impairment. First aid after intake of toxic doses: induce vomiting at once or gastric lavage, if necessary haemodialysis. Monitor and if necessary correct the water and electrolyte balance, monitor renal function.

ATC classification

ATC-Code: J01DB05

Pharmacotherapeutic group: Other beta-lactam antibacterials. First generation cephalosporins.

Mode of action

B.d Roxil is a cephalosporin for oral administration which inhibits bacterial wall synthesis of actively dividing cells by binding to one or more penicillin-binding proteins. The result is formation of a defective cell wall that is osmotically unstable, and bacterial cell lysis.

Mechanisms of resistance

B.d Roxil may be active against organisms producing some types of beta-lactamase, for example TEM-1, in low to moderate quantities. However, it is inactivated by beta-lactamases that can efficiently hydrolyse cephalosporins, such as many of the extended-spectrum beta-lactamases and chromosomal cephalosporinases, such as AmpC type enzymes.

B.d Roxil cannot be expected to be active against bacteria with penicillin-binding proteins that have reduced affinity for beta-lactam drugs. Resistance may also be mediated by bacterial impermeability or by bacterial drug efflux pumps. More than one of these four means of resistance may be present in the same organism.

In vitro, oral first generation cephalosporins are less active than penicillins G and V on Gram-positive microorganisms and are less active than aminopenicillins on H. influenzae.

Breakpoints

The following breakpoint recommendations for B.d Roxil according to the European Committee on Antimicrobial Susceptibly Testing (EUCAST) have been defined (Breakpoint tables for interpretation of MICs and zone diameters, Version 1.0, December 2009):

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

Note²: The beta-lactam susceptibility of beta-haemolytic streptococci groups A, B, C and G is inferred from the penicillin susceptibility.

IE: indicates that there is insufficient evidence that the species in question is a good target for therapy with the drug.

Susceptibility

The prevalence of 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.

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications

^$ Species with natural intermediate susceptibility

Absorption

After oral administration B.d Roxil is practically completely absorbed. Simultaneous intake of food has practically no effect on absorption (AUC).

Distribution

After oral doses of 500 mg (1000 mg) peak plasma concentrations of about 16 (30) μg/ml are obtained after 1-1,3 hours. Between 18 and 20% of B.d Roxil is bound to plasma proteins. Cephalosporins do not penetrate in the CSF and should not be used for treatment of meningitis

Biotransformation

B.d Roxil is not metabolised.

Elimination

B.d Roxil is eliminated far more slowly than comparable oral cephalosporins (half life: about 1,4 h to 2,6 h) so that intervals between doses can be prolonged to 12-24 hours. Roughly 90% of the substance is eliminated in unchanged form through the kidneys within 24 hours. B.d Roxil may be eliminated from the organism through haemodialysis.

Characteristics in patients with reduced creatinine clearance, a sign for renal functional impairment

Elimination is retarded, so that interval between doses must be prolonged.

Not applicable.

No special requirements.