No clinical reports are as yet available on Medambenil 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.
-
- History of severe reactions to penicillins or to any other beta-lactam drugs.
Not applicable.
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.
| System Organ Class | 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 |
| Infections and infestations | Clinical pictures due to a growth of opportunistic organisms (fungi), such as vaginal mycoses, thrush. | |||
| Blood and lymphatic system disorders | Eosinophilia, thrombocytopenia, leucopenia, neutropenia, agranulocytosis: rare cases during prolonged used, which subside upon discontinuation of therapy. | Haemolytic anemia of immunologic origin. | ||
| Immune system disorders | Serum sickness-like reactions. | Immediate allergic reaction (anaphylactic shock). | ||
| Nervous system disorders | Headache, sleeplessness, dizziness, nervousness. | |||
| Gastrointestinal disorders | Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, glossitis. | Pseudomenbranous colitis has been reported (may range in severity from mild to life threatening). | ||
| Hepatobiliary disorders | Cholestase and idiosyncratic hepatic failure have been reported. Minor elevation of serum transaminases (ASAT, ALAT) and alcaline phosphatases. | |||
| Skin and subcutaneous tissue disorders | Pruritus, rash, allergic exanthema, urticaria. | Angioneurotic edema. | Stevens Johnson syndrom and erythema multiforma have been reported. | |
| Musculoskeletal and connective tissue disorders | Arthralgia. | |||
| Renal and urinary disorders | Interstitial nephritis. | |||
| General disorders and administration site conditions | Drug fever. | Fatigue. | ||
| Investigations | Direct and indirect positive Coombs tests. |
*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.
Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and toxicity to reproduction.
Treatment of following infections caused by Medambenil-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.
ATC classification
ATC-Code: J01DB05
Pharmacotherapeutic group: Other beta-lactam antibacterials. First generation cephalosporins.
Mode of action
Medambenil 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
Medambenil 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.
Medambenil 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 Medambenil 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):
| Medambenil (EUCAST Clinical Breakpoint Table) | MIC breakpoints | |
| S ≤ | R > | |
| Enterobacteriaceae (uncomplicated UTI only) | 16 | 16 |
| Staphylococcus spp. | Note1 | Note1 |
| Streptococcus groups A, B, C, and G | Note2 | Note2 |
| Non-species related breakpoints | IE | IE |
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.
| Species | |
| Commonly susceptible species Gram-positive aerobes Streptococci Group B, C and G Streptococcus pyogenes * Gram-negative aerobes Moraxella catarrhalis * Species for which acquired resistance may be a problem Gram-positive aerobes Staphylococcus aureus (methicillin-susceptible) * Staphylococcus epidermidis Streptococcus pneumoniae * Gram-negative aerobes Citrobacter diversus$ Escherichia coli $ Haemophilus influenza $ Klebsiella pneumoniae$ Klebsiella oxytoca$ Proteus mirabilis* $ Inherently resistant species Gram-positive aerobes Enterococcus spp. Staphylococcus aureus (methicillin-resistant) Staphylococcus epidermidis (methicillin-resistant) Streptococcus pneumoniae (penicillin-resistant) Gram-negative aerobes Acinetobacter spp. Citrobacter freundii Enterobacter spp. Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Serratia marcescens Other species Chlamydia spp Mykoplasma spp Legionella spp |
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
$ Species with natural intermediate susceptibility
Absorption
After oral administration Medambenil 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 Medambenil is bound to plasma proteins. Cephalosporins do not penetrate in the CSF and should not be used for treatment of meningitis
Biotransformation
Medambenil is not metabolised.
Elimination
Medambenil 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. Medambenil 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.
- Medambenil 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 Medambenil 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, Medambenil 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. Medambenil 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 Medambenil.
- In case of severe and persistent diarrhoea, an antibiotic-associated pseudomembranous colitis should be considered. In that case Medambenil 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 Medambenil. 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 Medambenil blood levels.
- Urinary sugar should be determined enzymatically (e.g. with test strips) during treatment with Medambenil since reduction tests can furnish falsely elevated values.
Medambenil may cause headache, dizziness, nervousness, sleeplessness and fatigue, therefore the ability to drive and use machines may be influenced.
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).
| Indication | Adults and adolescents > 40 kg with normal renal function | Children (< 40 kg) with normal renal function |
| Streptococcal pharyngitis / tonsillitis | Dosage may be decreased to 1000 mg once a day over at least 10 days | 30 mg/kg/day once a day over at least 10 days |
| Bronchopneumonia, bacterial pneumonia | 1000 mg twice a day | 30-50 mg/kg/day divided into two daily doses |
| Urinary tract infections
| 1000 mg twice a day | 30-50 mg/kg/day divided into two daily doses |
| Skin & soft tissue infections
| 1000 mg twice a day | 30-50 mg/kg/day divided into two daily doses |
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.
Medambenil 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 (Medambenil 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 Medambenil. In patients with creatinine clearance of 50 ml/min or less, the following reduced dosage schedule is recommended as a guideline for adults:
| Creatinine clearance (ml/ min/ 1.73 m2) | Serum Creatinine (mg/100ml) | Initial dose | Following dose | Dosage interval |
| 50 - 25 | 1.4 - 2.5 | 1000 mg | 500 mg - 1000 mg | every 12 hours |
| 25 - 10 | 2.5 - 5.6 | 1000 mg | 500 mg - 1000 mg | every 24 hours |
| 10 - 0 | > 5.6 | 1000 mg | 500 mg - 1000 mg | every 36 hours |
- Children (< 40 kg) with renal impairment:
Medambenil 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 Medambenil 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 Medambenil 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.
No special requirements.
