Loxamox solution for infusion is indicated in adults for the treatment of the following infections
(see sections 4.4 and 5.1):
• Community-acquired pneumonia
• Complicated skin and soft tissue infections
For the above-mentioned infections Loxamox should be used only when it is considered
inappropriate to use antibacterial agents that are commonly recommended for the initial
treatment of these infections
• Pyelonephritis and complicated urinary tract infections (see section 4.4)
• Chronic bacterial prostatitis
• Inhalation anthrax: postexposure prophylaxis and curative treatment (see section 4.4)
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Loxamox solution is administered by slow intravenous infusion once or twice daily. The dosage
depends in the type and severity of the infection and the susceptibility of the presumed causative
pathogen. Treatment with Loxamox after the initial use of the intravenous preparation may be
completed with an appropriate oral Loxamox presentation, in accordance with its SPC, and as
considered appropriate for the individual patient. Given the bioequivalence of the parenteral and
oral forms, the same dosage can be used.
Posology
The following dose recommendations can be given for Loxamox:
Dosage in patients with normal renal function (creatinine clearance > 50 ml/min)

(including
haemodialysis and
CAPD) 1

1No additional doses are required after haemodialysis or continuous ambulatory peritoneal
dialysis (CAPD).
Patients with hepatic impairment
No adjustment of dose is required since Loxamox is not metabolised to any relevant extent by
the liver and is mainly excreted by the kidneys.
Older people
No adjustment of dose is required in the elderly, other than that imposed by consideration of
renal function (see section 4.4 'tendinitis and tendon rupture' and 'QT interval prolongation').
Paediatric population
Loxamox is contraindicated in children and growing adolescents (see section 4.3).
Method of administration
Loxamox solution for infusion is only intended for slow intravenous infusion; it is administered
once or twice daily. The infusion time must be at least 30 minutes for 250 mg or 60 minutes for
500 mg Loxamox (see section 4.4).
For incompatibilities see 6.2 and compatibility with other infusion solutions see 6.6.

 

Loxamox 5 mg/ml Solution for Infusion must not be used: • in patients hypersensitive to Loxamox, to any other quinolones or to any of the excipients listed in section 6.1 • in patients with epilepsy • in patients with history of tendon disorders related to fluoroquinolone administration • in children or growing adolescents • during pregnancy • in breast-feeding women

Methicillin-resistant Staphylococcus aureus (MRSA) are very likely to possess co-resistance to fluoroquinolones, including Loxamox. Therefore, Loxamox is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to Loxamox (and commonly recommended antibacterial agents for
the treatment of MRSA infections are considered inappropriate).
Resistance to fluoroquinolones of E. Coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.
Inhalation Anthrax: Use in humans is based on in vitro Bacillus anthracis susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.
Infusion time
The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for 500 mg Loxamox should be observed. It is known for ofloxacin, that during infusion tachycardia and a temporary decrease in blood pressure may develop. In rare cases, as a consequence of a profound drop in blood pressure, circulatory collapse may occur. Should a conspicuous drop in blood pressure occur during infusion of Loxamox, (l-isomer of ofloxacin) the infusion must be halted immediately.
Sodium content
This medicinal product contains 15.4 mmol (354 mg) sodium per 100 ml dose and 7.7 mmol (177 mg) sodium per 50 ml dose. To be taken into consideration by patients on a controlled sodium diet.
Tendinitis and tendon rupture
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with Loxamox and have been reported up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years, in patients receiving daily doses of 1000mg and in patients using corticosteroids. The daily dose should be adjusted in elderly patients based on creatinine clearance (see Section 4.2) Close monitoring of these patients is therefore necessary if they are prescribed Loxamox. All patients should consult their physician if they experience symptoms of
tendinitis. If tendinitis is suspected, treatment with Loxamox must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon (see sections 4.3 and 4.8)

Clostridium difficile-associated disease
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Loxamox, (including several weeks after treatment) may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life threatening,
the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with Loxamox. If CDAD is suspected or confirmed, Loxamox should be stopped immediately and appropriate treatment initiated without delay. Anti-peristaltic medicinal products are contraindicated in this clinical situation.
Patients predisposed to seizures
Quinolones may lower the seizure threshold and may trigger seizures. Loxamox is
contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures, or concomitant treatment with active substances which lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures, (see section 4.8), treatment with Loxamox should be discontinued.
Patients with G-6- phosphate dehydrogenase deficiency

Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions when treated with quinolone antibacterial agents. Therefore, if Loxamox has to be used in these patients, potential occurrence of haemolysis should be monitored.
Patients with renal impairment
Since Loxamox is excreted mainly by the kidneys, the dose medicinal product should be adjusted in patients with renal impairment (see section 4.2).
Hypersensitivity reactions
Loxamox can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to anaphylactic shock), occasionally following the initial dose (see section 4.8). Patients should discontinue treatment immediately and contact their physician or an emergency physician, who will initiate appropriate emergency measures.

Severe bullous reactions
Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with Loxamox (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Dysglycaemia
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
Prevention of photosensitisation
Photosensitisation has been reported with Loxamox (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial ultraviolet (UV) rays (e.g. sunray lamp, solarium), during treatment and for 48 hours following treatment discontinuation, in order to prevent photosensitisation.
Patients treated with Vitamin K antagonists
Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with Loxamox in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomitantly (see section 4.5).
Psychotic reactions
Psychotic reactions have been reported in patients receiving quinolones, including Loxamox. In very rare cases these have progressed to suicidal thoughts and self-endangering behaviour - sometimes after only a single dose of Loxamox (see section 4.8). In the event that the patient develops these reactions, Loxamox should be discontinued and appropriate measures instituted.
Caution is recommended if Loxamox is to be used in psychotic patients or in patients with history of psychiatric disease.
QT interval prolongation
Caution should be taken when using fluoroquinolones, including Loxamox, in patients with known risk factors for prolongation of the QT interval such as, for example:
- congenital long QT syndrome

- concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
- uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)
- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
- elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including Loxamox, in these populations. (See section 4.2 Elderly, 4.5, 4.8, and 4.9).
Peripheral neuropathy
Peripheral sensory neuropathy and peripheral motor sensory neuropathy have been reported in patients receiving fluoroquinolones, including Loxamox, which can be rapid in its onset (see section 4.8). Loxamox should be discontinued if the patient experiences symptoms of neuropathy
in order to prevent the development of an irreversible condition.
Hepatobiliary disorders
Cases of hepatic necrosis up to fatal hepatic failure have been reported with Loxamox, primarily in patients with severe underlying diseases, e.g. sepsis (see section 4.8). Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Exacerbation of myasthenia gravis
Fluoroquinolones, including Loxamox, have neuromuscular blocking activity and may
exacerbate muscle weakness in patients with myasthenia gravis. Post marketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Loxamox is not recommended in patients with a known history of myasthenia gravis.
Vision disorders
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).
Superinfection
The use of Loxamox, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Vascular disorders
Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.
Therefore, fluoroquinolones should only be used after careful benefit/risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis,
Behcet's disease, hypertension, known atherosclerosis).
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department (see section 4.8)
Interference with laboratory tests
In patients treated with Loxamox, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method. Loxamox may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give falsenegative results in the bacteriological diagnosis of tuberculosis.

 

Effect of other medicinal products on Loxamox
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions of Loxamox were found with theophylline in a clinical study.
However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other agents which lower the seizure threshold.
Loxamox concentrations were about 13% higher in the presence of fenbufen than when administered alone.
Probenecid and cimetidine
Probenecid and cimetidine had a statistically significant effect on the elimination of Loxamox.
The renal clearance of Loxamox was reduced by cimetidine (24%) and probenecid (34%). This is because both drugs are capable of blocking the renal tubular secretion of Loxamox. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.

Caution should be exercised when Loxamox is coadministered with drugs that effect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
Other relevant information
Clinical pharmacology studies have shown that the pharmacokinetics of Loxamox were not affected to any clinically relevant extent when Loxamox was administered together with the following drugs: calcium carbonate, digioxin, glibenclamide, ranitidine.
Effect of Loxamox on other medicinal products
Ciclosporin
The half-life of ciclosporin was increased by 33% when coadministered with Loxamox.
Vitamin K antagonists
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with Loxamox in combination with a vitamin K antagonist (e.g. warfarin).
Coagulation tests, therefore, should be monitored in patients treated with vitamin K antagonists (see section 4.4).
Drugs known to prolong QT interval
Loxamox, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics). (See section 4.4 QT interval prolongation).
Other relevant information
In a pharmacokinetic interaction study, Loxamox did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating that Loxamox is not a CYP1A2 inhibitor

Pregnancy
There are limited amount of data on the use of Loxamox in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3) However in the absence of human data and since experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism Loxamox must not be used during pregnancy (see sections 4.3 and 5.3).
Breast Feeding 

Loxamox is contraindicated in breast-feeding women. There is insufficient evidence on the excretion of Loxamox in human milk, however other fluoroquinolones are excreted in human breast milk. In the absence of human data and since experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Loxamox must not be used in breast-feeding women (see sections 4.3 and 5.3).
Fertility
Loxamox caused no impairment of fertility or reproductive performance in rats.

Some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) may impair the patient's ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

The information given below is based on data from clinical studies in more than 8300 patients and on extensive post marketing experience.
Frequencies in this table are defined using the following convention:
Very common (≥1/10),
Common (≥1/100 to <1/10),
Uncommon (≥1/1000 to <1/100),
Rare (≥1/10000 to <1/1000),
Very rare: (< 1/10000) ,
Not known ( Cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

aAnaphylactic and anaphalactoid reactions may sometimes occur, even after the first dose
bMucocutaneous reactions may sometimes occur even after the first dose
Other undesirable effects which have been associated with fluoroquinolone administration include:
• Attacks of porphyria in patients with porphyria.

 

 

 

According to toxicity studies in animals or clinical pharmacology studies performed with supratherapeutic doses, the most important signs to be expected following acute overdose of Loxamox are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval.
CNS effects including confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing Loxamox from the body.
No specific antidote exists.

Pharmacotherapeutic group:
ATC Code: Quinolone antibacterials - Fluoroquinolones
J01MA12
Loxamox is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-)
enantiomer of the racemic drug substance ofloxacin.
Mechanism of action
As a fluoroquinolone antibacterial agent, Loxamox acts on the DNA-DNA-gyrase complex and topoisomerase IV.
PK/PD relationship
The degree of the bactericidal activity of Loxamox depends on the ratio of the maximum concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).
Mechanism of resistance
Resistance to Loxamox is acquired through a stepwise process by target site mutations in bothType II topoisomerases, DNA gyrase and topisomerase IV. Other resistance mechanisms, such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also affect susceptibility to Loxamox.

Cross-resistance between Loxamox and other fluoroquinolones is observed. Due to the mechanism of action , there is generally no cross-resistance between Loxamox and other classes of antibacterial agents.
Breakpoints
The EUCAST recommended MIC breakpoints for Loxamox, separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in the below table for MIC testing (mg/L):
EUCAST clinical MIC breakpoints for Loxamox Version 2.0, 2012-01-01

1 The breakpoints for Loxamox relate to high dose therapy.
2 Low-level fluoroquinolone resistance (ciprofloxacin MIC's of 0.12-0.5 mg/L) may occur but there is no evidence that this resistance is of clinical importance in respiratory tract infections with H. influenzae.
3Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.
4 Breakpoints apply to an oral dose of 500mg x1 to 500mg x2 and an intravenous dose of 500mg x 1 to 500mg x 2.

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.
COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive bacteria
Bacillus anthracis
Staphylococcus aureus methicillin-susceptible
Staphylococcus saprophyticus
Streptococci, groups C and G
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic Gram-negative bacteria
Eikenella corrodens
Haemophilus influenzae
Haemophilus para-influenzae
Klebsiella oxytoca
Moraxella catarrhalis
Pasteurella multocida
Proteus vulgaris
Providencia rettgeri
Anaerobic bacteria
Peptostreptococcus
Other
Chlamydophila pneumoniae
Chlamydophila psittaci
Chlamydia trachomatis
Legionella pneumophila
Mycoplasma pneumoniae
Mycoplasma hominis

Ureaplasma urealyticum
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive bacteria
Enterococcus faecalis
Staphylococcus aureus methicillin-resistant#
Coagulase negative Staphylococcusspp
Aerobic Gram-negative bacteria
Acinetobacter baumannii
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Morganella morganii
Proteus mirabilis
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
Anaerobic bacteria
Bacteroides fragilis
Inherently Resistant Strains
Aerobic Gram-positive bacteria
Enterococcus faecium
# Methicilin-resistant S.aureus are very likely to possess co-resistance to fluoroquinolones, including Loxamox.
 

Absorption
Orally administered Loxamox is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1-2 h. The absolute bioavailability is 99 to 100 %.
Food has little effect on the absorption of Loxamox.

Steady state conditions are reached within 48 hours following a 500mg once or twice daily dosage regimen.
Distribution
Approximately 30 - 40 % of Loxamox is bound to serum protein.
The mean volume of distribution of Loxamox is approximately 100l after single and repeated 500mg doses, indicating widespread distribution into body tissues.
Penetration into tissues and body fluids:
Loxamox has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, Loxamox has poor penetration into cerebro-spinal fluid
Biotransformation
Loxamox is metabolised to a very small extent, the metabolites being desmethyl-Loxamox and Loxamox N-oxide. These metabolites account for < 5 % of the dose excreted in urine. Loxamox is stereochemically stable and does not undergo chiral inversion.
Elimination
Following oral and intravenous administration of Loxamox, it is eliminated relatively slowly from the plasma (t½: 6 - 8 h). Excretion is primarily by the renal route (> 85 % of the administered dose).
The mean apparent total body clearance of Loxamox following a 500mg single dose was 175+/- 29.2 ml/min.
There are no major differences in the pharmacokinetics of Loxamox following intravenous and oral administration, suggesting that the oral and intravenous routes are interchangeable.
Linearity
Loxamox obeys linear pharmacokinetics over a range of 50 to 1000 mg.
Special Populations
Subjects with renal insufficiency
The pharmacokinetics of Loxamox are affected by renal impairment. With decreasing renal function renal elimination and clearance are decreased, and elimination half-lives increased as shown in the table below:
Pharmacokinetics in renal insufficiency following single oral 500mg dose

Clcr [ml/min] < 20 20 - 40 50 - 80
ClR [ml/min] 13 26 57
t1/2 [h] 35 27 9

Elderly subjects
There are no significant differences in Loxamox kinetics between young and elderly subjects, except those associated with differences in creatinine clearance.
Gender differences Separate analysis for male and female subjects showed small to marginal gender differences in Loxamox pharmacokinetics. There is no evidence that these gender differences are of clinical relevance.

 

Non clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity to reproduction and development.
Loxamox caused no impairment of fertility or reproductive performance in rats, and its only effect on foetuses was delayed maturation as a result of maternal toxicity.
Loxamox did not induce gene mutations in bacterial or mammalian cells but did induce chromosome aberrations in Chinese hamster lung (CHL) cells in vitro. These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.
Studies in the mouse showed Loxamox to have phototoxic activity only at very high doses. Loxamox did not show any genotoxic potential in a photomutagenicity assay, and it reduced tumour development in a photocarcinogenicity assay.
In common with other fluoroquinolones, Loxamox showed effects on cartilage (blistering and cavities) in rats and dogs. These findings were more marked in young animals.

Sodium chloride
Hydrochloric acid (for pH adjustment)
Water for Injections

This medicinal product must not be mixed with heparin or alkaline solutions (e.g. sodium hydrogen carbonate). This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

2 years. Shelf life after opening : immediate use see section 6.6. From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Do not store above 30°C.
Keep the bags in the foil wrap in order to protect from light.
For storage conditions of the diluted product see section 6.3.

Polyolefin Bags 100ml with Plug for bag

Loxamox solution for infusion should be used immediately (within 3 hours) .
This product is for single use only.
No protection from light is necessary during infusion.
Any unused product or waste material should be disposed of in accordance with local
requirements.
Mixture with other solutions for infusion:
Levofloxacin 5mg/ml Solution for Infusion is compatible with the following solutions for infusion:
• Sodium chloride 9 mg/ml (0.9%) solution

• Dextrose 50 mg/ml (5%) injection
• Dextrose 25 mg/ml (2.5%) in Ringer's solution
• Combination solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).
The solution should be visually inspected prior to use. It must only be used if the solution is clear, greenish-yellow solution, practically free from particles.