An overdose of 12 g has been reported to lead to mild symptoms of toxicity. An acute overdose of 16 g has been reported to cause acute renal failure.
Symptoms in overdose consist of dizziness, tremor, headache, tiredness, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic impairment as well as crystalluria and haematuria. Reversible renal toxicity has been reported.
Apart from routine emergency measures, e.g. ventricular emptying followed by medical carbon, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of Basemar in overdoses.
Only a small quantity of Basemar (< 10%) is eliminated by haemodialysis or peritoneal dialysis.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.
Unless compatibility with other solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding, and discoloration.
Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solutions (e.g. penicillins, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of Basemar solutions: 3.9 - 4.5).
The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhea, vomiting, transient increase in transaminases, rash, and injection and infusion site reactions.
ADRs derived from clinical studies and post-marketing surveillance with Basemar (oral, intravenous and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of Basemar.
| 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) | Frequency not known (cannot be estimated from the available data) |
| Infections and infestations | Mycotic superinfections | ||||
| Blood and lymphatic system disorders | Eosinophilia | Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia | Haemolytic anaemia Agranulocytosis Pancytopenia (life-threatening) Bone marrow depression (life-threatening) | ||
| Immune system disorders | Allergic reaction Allergic oedema / angioedema | Anaphylactic reaction Anaphylactic shock (life-threatning) Serum sickness-like reaction | |||
| Metabolism and nutrition disorders | Decreased appetite | Hyperglycaemia Hypoglycaemia | |||
| Psychiatric disorders | Psychomotor hyperactivity / agitation | Confusion and disorientation Anxiety reaction Abnormal dreams Depression (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) Hallucinations | Psychotic reactions (potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) | Mania, hypomania | |
| Nervous system disorders | Headache Dizziness Sleep disorders Taste disorders | Par- and dysaesthesia Hypoaesthesia Tremor Seizures Vertigo | Migraine disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension and pseudotumor cerebri | Peripheral neuropathy | |
| Eye disorders | Visual disturbances (e.g. diplopia) | Visual colour distortions | |||
| Ear and labyrinth disorders | Tinnitus Hearing loss / hearing impaired | ||||
| Cardiac disorders | Tachycardia | Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged | |||
| Vascular disorders | Vasodilatation Hypotension Syncope | Vasculitis | |||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea (including asthmatic condition) | ||||
| Gastrointestinal disorders | Nausea Diarrhoea | Vomiting Gastrointestinal and abdominal pains Dyspepsia Flatulence | Antibiotic associated colitis (very rarely with possible fatal outcome) | Pancreatitis | |
| Hepatobiliary disorders | Increase in transaminases Increased bilirubin | Hepatic impairment Cholestatic icterus Hepatitis | Liver necrosis (very rarely progressing to life-threatening hepatic failure) | ||
| Skin and subcutaneous tissue disorders | Rash Pruritus Urticaria | Photosensitivity reactions | Petechia Erythema multiforme Erythema nodosum Stevens-Johnson syndrome (potentially life-threatening) Toxic epidermal necrolysis (potencially life-threatening) | Acute generalised exanthematous pustulosis (AGEP), DRESS | |
| Musculoskeletal, connective tissue and bone disorders | Musculoskeletelal pain (e.g. extremity pain, back pain, chest pain) Arthralgia | Myalgia Arthritis Increased muscle tone and cramping | Muscular weakness Tendinitis Tendon rupture (predominantly Achilles tendon) Exacerbation of symptoms of myasthenia gravis | ||
| Renal and urinary disorders | Renal impairment | Renal failure Haematuria Crystalluria Tubulointerstitial nephritis | |||
| General disorders and administration site conditions | Injection and infusion site reactions (only intravenous administration) | Asthenia Fever | Oedema Sweating (hyperhidrosis) | ||
| Investigations | Increase in blood alkaline phosphatase | Increase amylase | International normalised ratio increased (in patients treated with Vitamin K antagonists) |
The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment:
| Common | Vomiting Transient increase in transaminases Rash |
| Uncommon | Thrombocytopenia Thrombocytaemia Confusion and disorientation Hallucinations Par- and dysaesthesia Seizures Vertigo Visual disturbances Hearing loss Tachycardia Vasodilatation Hypotension Transient hepatic impairment Cholestatic icterus Renal failure Oedema |
| Rare | Pancytopenia Bone marrow depression Anaphylactic shock Psychotic reactions Migraine Olfactory nerve disorders Hearing impaired Vasculitis Pancreatitis Liver necrosis Petechiae Tendon rupture |
Paediatric population
The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly.
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 - Website: www.mhra.gov.uk/yellowcard.
Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction.
Like a number of other quinolones, Basemar is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity / photocarcinogenicity show a weak photomutagenic or phototumorigenic effect of Basemar in-vitro and in animal experiments. This effect was comparable to that of other gyrase inhibitors.
Articular tolerability
As reported for other gyrase inhibitors, Basemar causes damage to the large weight-bearing joints in immature animals. The extent of the cartilage damage varies according to age, species and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs, Basemar caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months.
Pharmacotherapeutic group: Fluoroquinolones, ATC code: J01MA02
Mechanism of action
As a fluoroquinolone antibacterial agent, the bactericidal action of Basemar results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.
Pharmacokinetic/pharmacodynamic relationship
Efficacy mainly depends on the relation between the maximum concentration in serum (Cmax) and the minimum inhibitory concentration (MIC) of Basemar for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.
Mechanism of resistance
In-vitro resistance to Basemar can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of cross-resistance between Basemar and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or all active substances within the class.
Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in-vitro mechanisms of resistance are commonly observed in clinical isolates.
Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to Basemar.
Plasmid-mediated resistance encoded by qnr-genes has been reported.
Spectrum of antibacterial activity
Breakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:
EUCAST Recommendations
| Microorganisms | Susceptible | Resistant |
| Enterobacteriaceae | S ≤ 0.5 mg/l | R > 1 mg/l |
| Pseudomonas spp. | S ≤ 0.5 mg/l | R > 1 mg/l |
| Acinetobacter spp. | S ≤ 1 mg/l | R > 1 mg/l |
| Staphylococcus spp.1 | S ≤ 1 mg/l | R > 1 mg/l |
| Haemophilus influenzae and Moraxella catarrhalis | S ≤ 0.5 mg/l | R > 0.5 mg/l |
| Neisseria gonorrhoeae | S ≤ 0.03 mg/l | R > 0.06 mg/l |
| Neisseria meningitidis | S ≤ 0.03 mg/l | R > 0.06 mg/l |
| Non-species-related breakpoints* | S ≤ 0.5 mg/l | R > 1 mg/l |
1 Staphylococcus spp. - breakpoints for Basemar relate to high dose therapy.
* Non-species-related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended.
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.
Groupings of relevant species according to Basemar susceptibility
| COMMONLY SUSCEPTIBLE SPECIES |
| Aerobic Gram-positive micro-organisms Bacillus anthracis (1) |
| Aerobic Gram-negative micro-organisms Aeromonas spp. Brucella spp. Citrobacter koseri Francisella tularensis Haemophilus ducreyi Haemophilus influenzae* Legionella spp. Moraxella catarrhalis* Neisseria meningitidis Pasteurella spp. Salmonella spp.* Shigella spp. * Vibrio spp. Yersinia pestis |
| Anaerobic micro-organisms Mobiluncus |
| Other micro-organisms Chlamydia trachomatis () Chlamydia pneumoniae () Mycoplasma hominis () Mycoplasma pneumoniae () |
| SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM |
| Aerobic Gram-positive micro-organisms Enterococcus faecalis () Staphylococcus spp. *(2) |
| Aerobic Gram-negative micro-organisms Acinetobacter baumannii+ Burkholderia cepacia +* Campylobacter spp.+* Citrobacter freundii* Enterobacter aerogenes Enterobacter cloacae * Escherichia coli* Klebsiella oxytoca Klebsiella pneumoniae* Morganella morganii* Neisseria gonorrhoeae* Proteus mirabilis* Proteus vulgaris* Providencia spp. Pseudomonas aeruginosa* Pseudomonas fluorescens Serratia marcescens* |
| Anaerobic micro-organisms Peptostreptococcus spp. Propionibacterium acnes |
| INHERENTLY RESISTANT ORGANISMS |
| Aerobic Gram-positive micro-organisms Actinomyces Enteroccus faecium Listeria monocytogenes |
| Aerobic Gram-negative micro-organisms Stenotrophomonas maltophilia |
| Anaerobic micro-organisms Excepted as listed above |
| Other micro-organisms Mycoplasma genitalium Ureaplasma urealitycum |
| * Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications. + Resistance rate > 50% in one or more EU countries. (): Natural intermediate susceptibility in the absence of acquired mechanism of resistance. (1): Studies have been conducted in experimental animal infections due to inhalations of Bacillus anthracis spores; these studies reveal that antibiotics starting early after exposition avoid the occurrence of the disease if the treatment is made up to the decrease of the number of spores in the organism under the infective dose. The recommended use in human subjects is based primarily on in-vitro susceptibility and on animal experimental data together with limited human data. Two-month treatment duration in adults with oral Basemar given at the following dose, 500 mg bid, is considered as effective to prevent anthrax infection in humans. The treating physician should refer to national and /or international consensus documents regarding treatment of anthrax. (2): Methicillin-resistant S. aureus very commonly express co-resistance to fluoroquinolones. The rate of resistance to methicillin is around 20 to 50% among all staphylococcal species and is usually higher in nosocomial isolates. |
Absorption
Following an intravenous infusion of Basemar the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of Basemar were linear over the dose range up to 400 mg administered intravenously.
Comparison of the pharmacokinetic parameters for a twice a day and three times a day intravenous dose regimen indicated no evidence of drug accumulation for Basemar and its metabolites.
A 60-minute intravenous infusion of 200 mg Basemar or the oral administration of 250 mg Basemar, both given every 12 hours, produced an equivalent area under the serum concentration time curve (AUC).
A 60-minute intravenous infusion of 400 mg Basemar every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC.
The 400 mg intravenous dose administered over 60 minutes every 12 hours resulted in a Cmax similar to that observed with a 750 mg oral dose.
A 60-minute infusion of 400 mg Basemar every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.
Distribution
Protein binding of Basemar is low (20-30%). Basemar is present in plasma largely in a non-ionised form and has a large steady state distribution volume of 2-3 l/kg body weight. Basemar reaches high concentrations in a variety of tissues such as lung (epithelial fluid, alveolar macrophages, biopsy tissue), sinuses, inflamed lesions (cantharides blister fluid), and the urogenital tract (urine, prostate, endometrium) where total concentrations exceeding those of plasma concentrations are reached.
Biotransformation
Low concentrations of four metabolites have been reported, which were identified as: desethyleneBasemar (M 1), sulphoBasemar (M 2), oxoBasemar (M 3) and formylBasemar (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.
Basemar is known to be a moderate inhibitor of the CYP 450 1A2 iso-enzymes.
Elimination
Basemar is largely excreted unchanged both renally and, to a smaller extent, faecally.
| Excretion of Basemar (% of dose) | ||
| Intravenous administration | ||
| Urine | Faeces | |
| Basemar | 61.5 | 15.2 |
| Metabolites (M1 - M4) | 9.5 | 2.6 |
Renal clearance is between 180-300 ml/kg/h and the total body clearance is between 480-600 ml/kg/h. Basemar undergoes both glomerular filtration and tubular secretion. Severely impaired renal function leads to increased half lives of Basemar of up to 12 h.
Non-renal clearance of Basemar is mainly due to active trans-intestinal secretion and metabolism. 1% of the dose is excreted via the biliary route. Basemar is present in the bile in high concentrations.
Paediatric population
The pharmacokinetic data in paediatric patients are limited.
In a study in children Cmax and AUC were not age-dependent (above one year of age). No notable increase in Cmax and AUC upon multiple dosing (10 mg/kg three times daily) was observed.
In 10 children with severe sepsis Cmax was 6.1 mg/l (range 4.6-8.3 mg/l) after a 1-hour intravenous infusion of 10 mg/kg in children aged less than 1 year compared to 7.2 mg/l (range 4.7-11.8 mg/l) for children between 1 and 5 years of age. The AUC values were 17.4 mgh/l (range 11.8-32.0 mgh/l) and 16.5 mgh/l (range 11.0-23.8 mgh/l) in the respective age groups.
These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of paediatric patients with various infections, the predicted mean half-life in children is approx. 4-5 hours and the bioavailability of the oral suspension ranges from 50 to 80%.
Due to its neurological effects, Basemar may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.
The solution should be visually inspected prior to use and only clear solutions, without particles, should be used.
The infusion contains no preservatives. For single use only. Any remaining solution and vials and/or bags should be adequately disposed of, in accordance with local requirements.
Basemar is compatible with physiological sodium chloride solution, Ringer's solution, Ringer's lactate solution, 50 mg/ml (5 %) or 100 mg/ml (10 %) glucose solution and 50 mg/ml (5 %) glucose solution with 2.25 mg/ml (0.225 %) or 4.5 mg/ml (0.45 %) sodium chloride solution and 10% fructose solution. Compatibility with these solutions has been proven in Basemar concentrations of 1 mg/ml. Chemical and physical in-use stability has been demonstrated immediately after dilution, after 24 hours at 2-8°C and after 24 hours at room temperature. Unless compatibility is proven, the solution for infusion should always be administered separately.
The diluted solutions should be inspected visually for particulate matter and discoloration prior to administration. Only clear and colourless solutions should be used.
Handling glass vials:
Basemar 2 mg/ml may be infused via a suitable cannula directly or diluted with any of the fluids in the list above.
Handling plastic bags:
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product.
To open, tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.
