PAR Levofloxacin 250 and 500 mg Film-coated Tablets
UK/H/4331/001-2/DC
Public Assessment Report
Decentralised Procedure
Levofloxacin 250 mg and 500 mg Film-coated
Tablets
Levofloxacin hemihydrate
UK/H/4331/001-2/DC
UK licence no: PL 20075/0297-8
Accord Healthcare Limited
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LAY SUMMARY
On 11th May 2011, the Concerned Member States (CMSs) and the Reference Member State
(RMS) agreed to grant Marketing Authorisations to Accord Healthcare Limited for the
medicinal products Levofloxacin 250mg and 500mg Film-coated Tablets. The Marketing
Authorisations were granted via the Decentralised Procedure (DCP), with the UK as
Reference Member State (RMS). After the national phase, licences were granted in the UK
on 2nd June 2011. These medicines are only available on prescription from your doctor.
Levofloxacin tablet contains a drug called levofloxacin. Levofloxacin is an antibiotic which
is used to treat bacterial infections of the
- sinuses
- lungs e,g Pneumonia
- kidneys and waterworks
- prostate gland
- skin and soft tissue (including fat and muscle)
No new or unexpected safety concerns arose from these applications and it was, therefore,
judged that the benefits of taking Levofloxacin 250mg and 500mg Film-coated Tablets
outweigh the risks, hence Marketing Authorisations have been granted.
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TABLE OF CONTENTS
Module 1: Information about initial procedure
Page 4
Module 2: Summary of Product Characteristics
Page 5
Module 3: Product Information Leaflet
Page 29
Module 4: Labelling
Page 31
Module 5: Scientific Discussion
Page 35
I Introduction
II. Quality aspects
III. Non-clinical aspects
IV. Clinical aspects
V. Overall conclusion and Benefit-Risk Assessment
Module 6
Steps taken after initial procedure
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Module 1
Product Name
Levofloxacin 250 and 500mg Film-coated Tablets
Type of Application
Generic, Article 10.1
Active Substance
Levofloxacin hemihydrate
Form
Film-coated Tablets
Strength
250mg and 500mg
MA Holder
Accord Healthcare Limited
Sage House, 319, Pinner Road,
North Harrow, Middlesex,
HA1 4 HF,
United Kingdom
RMS
UK
CMS
Belgium, Bulgaria, Germany, Greece, Spain, France, Hungary,
Italy, Portugal and Romania
Procedure Numbers
UK/H/4331/001-2/DC
Timetable
Day 210 – 11th May 2011
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Module 2
SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Levofloxacin 250 mg Film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film coated tablet contains 250 mg of levofloxacin as active substance corresponding to 256.23
mg of levofloxacin hemihydrate.
For a full list of excipients, see section 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet
For 250 mg tablets: Pink coloured, capsule shaped, biconvex, film coated tablet with break line on both
sides. Debossed ‘L’ and ‘F’ either side of the break line on one face.
The tablets can be divided into equal halves.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
In adults with infections of mild or moderate severity, Levofloxacin Tablets are indicated for the
treatment of the following infections when due to levofloxacin-susceptible microorganisms: (see
section 5.1)
Acute sinusitis (adequately diagnosed according to national and/or local guidelines on the treatment of
respiratory tract infections, and when it is considered inappropriate to use antibacterial agents that are
commonly recommended for the initial treatment of this infection or when these have failed to resolve
the infection),
Acute exacerbations of chronic bronchitis (adequately diagnosed according to national and/or local
guidelines on the treatment of respiratory tract infections, and when it is considered inappropriate to
use antibacterial agents that are commonly recommended for the initial treatment of this infection or
when these have failed to resolve the infection),
Community-acquired pneumonia (when it is considered inappropriate to use antibacterial agents that
are commonly recommended for the initial treatment of this infection),
For 250mg only: Uncomplicated urinary tract infections
Complicated urinary tract infections (including pyelonephritis)
Chronic bacterial prostatitis.
Skin and soft tissue infections.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2
Posology and method of administration
Levofloxacin Tablets are administered once or twice daily. The dosage depends on the type and
severity of the infection and the sensitivity of the presumed causative pathogen.
Treatment time
The duration of therapy varies according to the course of the disease (see table below). As with
antibiotic therapy in general, administration of Levofloxacin Tablets should be continued for a
minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication
has been obtained.
Method of administration
Levofloxacin Tablets should be swallowed whole and with sufficient amount of liquid. The tablets may
be taken during meals or between meals. Levofloxacin Tablets should be taken at least two hours
before iron salts, antacids and sucralfate administration since reduction of absorption can occur (see
section 4.5).
The following dose recommendations can be given for Levofloxacin Tablets:
Dosage in patients with normal renal function
(creatinine clearance > 50 ml/min)
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Indication
Acute sinusitis
Acute exacerbations of chronic
bronchitis
Community-acquired pneumonia
Uncomplicated urinary tract
infections
Complicated urinary tract infections
including pyelonephritis
Chronic bacterial prostatitis
Skin and soft tissue infections
UK/H/4331/001-2/DC
Daily dose regimen (according
to severity)
500 mg once daily
Duration of
treatment
10 - 14 days
250 to 500 mg once daily
7 - 10 days
500 mg once or twice daily
7 - 14 days
250 mg once daily
3 days
250 mg once daily1
7 - 10 days
500 mg once daily
250 mg once daily or 500 mg
once or twice daily2
28 days
7 - 14 days
1,2
Consideration should be given to increasing the dose in cases of severe infection and special
attention should be paid to available information on resistance to levofloxacin before commencing
therapy.
1
Because of the increasing E.coli resistance the dose 500 mg/day should be considered.
2
Because of the increasing Staphylococcus resistance the dose 500 mg twice daily should be
considered.
Special Populations
Impaired renal function (creatinine clearance ≤ 50 ml/min)
Creatinine clearance
Dosage regimen
250 mg/24 h
First dose: 250 mg
Then:125 mg/24h
Then: 125 mg/48 h
500 mg/24 h
First dose: 500 mg
Then: 250 mg/24 h
Then: 125 mg/24 h
500 mg/12 h
First dose: 500 mg
Then:250 mg/12 h
Then:125 mg/12 h
50-20 ml/min
19-10 ml/min
< 10 ml/min (including
haemodialysis and
Then: 125 mg/48 h
Then: 125 mg/24 h
Then:125 mg/24 h
CAPD)1
1
No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis
(CAPD).
Impaired liver function
No adjustment of dosage is required since levofloxacin is not metabolised to any relevant extent by the
liver and is mainly excreted by the kidneys.
Dosage in elderly
No adjustment of dosage is required in the elderly, other than that imposed by consideration of renal
function (see section 4.4 QT interval prolongation).
In children
Levofloxacin is contraindicated in children and growing adolescents (less than 18 years of age) (see
section 4.3).
4.3
Contraindications
Levofloxacin Tablets must not be used:
in patients hypersensitive to levofloxacin or other quinolones or any of the excipients,
in patients with epilepsy,
in patients with history of tendon disorders related to fluoroquinolone administration,
in children or growing adolescents (up to age of 18)
during pregnancy,
in breast-feeding women.
4.4
Special warnings and precautions for use
In the most severe cases of pneumococcal pneumonia Levofloxacin Tablets may not be the optimal
therapy.
Nosocomial infections due to P. aeruginosa may require combination therapy.
Methicillin-resistant Staphylococcus aureus (MRSA)
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Levofloxacin is not effective against infections caused by MRSA (see section 5.1). In infections
suspicious for MRSA levofloxacin should be combined with an agent approved to treat MRSA
infections.
Tendinitis and tendon rupture
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon
rupture. The risk of tendinitis and tendon rupture is increased in the elderly and in patients using
corticosteroids. Close monitoring of these patients is therefore necessary if they are prescribed
Levofloxacin Tablets. All patients should consult their physician if they experience symptoms of
tendinitis. If tendinitis is suspected, treatment with Levofloxacin Tablets must be halted immediately,
and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.
Clostridium difficile-associated disease
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Levofloxacin
Tablets, may be symptomatic of Clostridium difficile-associated disease, the most severe form of which
is pseudomembranous enterocolitis. If pseudomembranous enterocolitis is suspected, Levofloxacin
Tablets must be stopped immediately and patients should be treated with supportive measures and
specific therapy without delay (e.g. oral metronidazole or vancomycin). Products inhibiting the
peristalsis are contraindicated in this clinical situation.
Patients predisposed to seizures
Levofloxacin Tablets are contraindicated in patients with a history of epilepsy and, as with other
quinolones, should be used with extreme caution in patients predisposed to seizures, such as patients
with pre-existing central nervous system damage; concomitant treatment with fenbufen and similar
non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such
as theophylline (see section 4.5). In case of convulsive seizures, treatment with levofloxacin 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, and so levofloxacin should be
used with caution.
Patients with renal impairment
Since levofloxacin is excreted mainly by the kidneys, the dose of Levofloxacin Tablets should be
adjusted in patients with renal impairment. (see section 4.2).
Hypersensitivity reactions
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema 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.
Hypoglycemia
As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving
concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with insulin. In these
diabetic patients, careful monitoring of blood glucose is recommended. (see section 4.8).
Prevention of photosensitisation
Although photosensitisation is very rare with levofloxacin, it is recommended that patients should not
expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp,
solarium), 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
levofloxacin 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 levofloxacin. In
very rare cases these have progressed to suicidal thoughts and self-endangering behaviour- sometimes
after only a single dose of levofloxacin (see section 4.8). In the event that the patient develops these
reactions, levofloxacin should be discontinued and appropriate measures instituted. Caution is
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recommended if levofloxacin is to be used in psychotic patients or in patients with a history of
psychiatric disease.
Cardiac disorders
Caution should be taken when using fluoroquinolones, including levofloxacin, 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).
- uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)
- elderly
- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
(see section 4.2 Elderly, section 4.5, section 4.8, section 4.9).
Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving
fluoroquinolones, including levofloxacin, which can be rapid in its onset. Levofloxacin should be
discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of
an irreversible condition.
Opiates
In patients treated with levofloxacin, determination of opiates in urine may give false-positive results.
It may be necessary to confirm positive opiate screens by a more specific method.
Hepatobiliary disorders
Cases of hepatic necrosis up to life threatening hepatic failure have been reported with levofloxacin,
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.
4.5
Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on levofloxacin
Iron salts, magnesium- or aluminium-containing antacids
Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminiumcontaining antacids are administered concomitantly. It is recommended that preparations containing
divalent or trivalent cations such as iron salts, or magnesium- or aluminium-containing antacids should
not be taken 2 hours before or after Levofloxacin Tablets administration (see section 4.2). No
interaction was found with calcium carbonate.
Sucralfate
The bioavailability of Levofloxacin Tablets is significantly reduced when administered together with
sucralfate. If the patient is to receive both sucralfate and Levofloxacin Tablets, it is best to administer
sucralfate 2 hours after the Levofloxacin Tablets administration (see section 4.2).
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions of levofloxacin 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.
Levofloxacin 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 levofloxacin. The
renal clearance of levofloxacin was reduced by cimetidine (24 %) and probenecid (34 %). This is
because both drugs are capable of blocking the renal tubular secretion of levofloxacin. 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 levofloxacin is coadministered with drugs that effect the tubular
renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
Effect of levofloxacin on other medicinal products
Ciclosporin
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The half-life of ciclosporin was increased by 33 % when coadministered with levofloxacin.
Vitamin K antagonists
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in
patients treated with levofloxacin 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 the QT interval
Levofloxacin, 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, antipsychotic). (See section 4.4 ).
Other forms of interactions
Meals
There is no clinically relevant interaction with food. Levofloxacin Tablets may therefore be
administered regardless of food intake.
Other relevant information
Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected
to any clinically relevant extent when levofloxacin was administered together with the following drugs:
calcium carbonate
digoxin
glibenclamide
ranitidine.
4.6
Pregnancy and lactation
Pregnancy
There are no data with respect to the use of levofloxacin in pregnant women. Animal studies do not
indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). In
juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been
observed; thus, it cannot be excluded that the drug could cause damage to articular cartilage in the
human immature organism / fetus (see section 5.3). The product is therefore contraindicated during
pregnancy.
Lactation
There is insufficient information with respect to the excretion of levofloxacin in human and/or animal
milk. In the absence of these data and given the potential risk of articular damage, levofloxacin is
contraindicated during breast-feeding.
4.7
Effects on ability to drive and use machines
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).
4.8
Undesirable effects
The information given below is based on data from clinical studies in more than 5000 patients and on
extensive post marketing experience.
The adverse reactions are described according to the MedDRA system organ class below.
Frequencies are defined using the following convention: very common (≥ 1/10), common (≥ 1/100, <
1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known
(cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Cardiac disorders
Rare: Tachycardia
Not Known: ventricular arrhythmia and torsades de pointes (reported predominantly in patients with
risk factors for QT prolongation), Electrocardiogram QT prolonged (see section 4.4 and section 4.9)
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Blood and lymphatic system disorders
Uncommon : Leukopenia, eosinophilia
Rare : Thrombocytopenia, neutropenia
Very rare : Agranulocytosis
Not Known : Pancytopenia, haemolytic anaemia
Nervous system disorders
Uncommon : Dizziness, headache, somnolence
Rare : Convulsion, tremor, paraesthesia,
Very rare: sensory or sensorimotor peripheral neuropathy, dysgeusia including ageusia, parosmia
including anosmia
Eye disorders
Very rare: Visual disturbance
Ear and Labyrinth disorders
Uncommon: Vertigo
Very rare: Hearing impaired
Not known: Tinnitus
Respiratory, thoracic and mediastinal disorders
Rare: Bronchospasm, dyspnoea
Very rare: Pneumonitis allergic
Gastrointestinal disorders
Common: Diarrhoea, nausea
Uncommon: Vomiting, abdominal pain, dyspepsia, flatulence, constipation
Rare: Diarrhoea –haemorrhagic which in very rare cases may be indicative of enterocolitis, including
pseudomembranous colitis
Renal and urinary disorders
Uncommon: Blood creatinine increased
Very rare: Renal failure acute (e.g. due to nephritis interstitial)
Skin and subcutaneous tissue disorders
Uncommon: Rash, pruritus
Rare: Urticaria
Very rare: Angioneurotic oedema, photosensitivity reaction
Not Known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme,
hyperhidrosis
Mucocutaneous reactions may sometimes occur even after the first dose
Musculoskeletal and Connective tissue disorders
Rare: Tendon disorder (see section 4.4) including tendinitis (e.g. Achilles tendon), arthralgia, myalgia
Very rare: Tendon rupture (see section 4.4). This undesirable effect may occur within 48 hours of
starting treatment and may be bilateral, muscular weakness which may be of special importance in
patients with myasthenia gravis
Not Known: Rhabdomyolysis
Metabolism and nutrition disorders
Uncommon: Anorexia
Very rare: Hypoglycemia, particularly in diabetic patients (see section 4.4)
Infections and infestations
Uncommon: Fungal infection (and proliferation of other resistant microorganisms)
Vascular disorders
Rare: Hypotension
General disorders and administration site conditions
Uncommon: Asthenia
Very rare: Pyrexia
Not known: Pain (including pain in back, chest, and extremities)
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Immune system disorders
Very rare: Anaphylactic shock (see section 4.4)
Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose
Not known: Hypersensitivity (see section 4.4)
Hepatobiliary disorders
Common: Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)
Uncommon: Blood bilirubin increased
Very rare: Hepatitis
Not known: Jaundice and severe liver injury, including cases with acute liver failure, have been
reported with levofloxacin, primarily in patients with severe underlying diseases (see section 4.4).
Psychiatric disorders
Uncommon: Insomnia, nervousness
Rare: Psychotic disorder, Depression, confusional state, agitation, anxiety
Very rare: Psychotic reactions with self-endangering behaviour including suicidal ideation or acts (see
section 4.4), hallucination
Other undesirable effects which have been associated with fluoroquinolone administration include:
extrapyramidal symptoms and other disorders of muscular coordination,
hypersensitivity vasculitis,
attacks of porphyria in patients with porphyria.
4.9
Overdose
According to toxicity studies in animals or clinical pharmacology studies performed with supratherapeutic doses, the most important signs to be expected following acute overdosage of levofloxacin
are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and
convulsive seizures, increases in QT interval as well as gastro-intestinal reactions such as nausea and
mucosal erosions.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be
undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection
of gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in
removing levofloxacin from the body. No specific antidote exists.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Anti-infective for systemic use – Antibacterials for systemic use –
Quinolone antibasterials – Fluoroquinolones
ATC code: J01MA12
Levofloxacin 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, levofloxacin acts on the DNA-DNA-gyrase complex and
topoisomerase IV.
PK/PD releationship
The degree of the bactericidal activity of levofloxacin 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(s) of resistance
The main mechanism of resistance is due to a gyr-A mutation. In vitro there is a cross-resistance
between levofloxacin and other fluoroquinolones.
Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other
classes of antibacterial agents.
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Breakpoints
The EUCAST recommended MIC breakpoints for levofloxacin, 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 levofloxacin (2006-06-20):
Pathogen
Susceptible
Resistant
Enterobacteriacae
≤1 mg/L
>2 mg/L
Pseudomonas spp.
≤1 mg/L
>2 mg/L
Acinetobacter spp.
≤1 mg/L
>2 mg/L
Staphylococcus spp.
≤1 mg/L
>2 mg/L
S.pneumoniae 1
≤2 mg/L
>2 mg/L
Streptococcus A,B,C,G
≤1 mg/L
>2 mg/L
H.influenzae M.catarrhalis 2
≤1 mg/L
>1 mg/L
Non-species related breakpoints 3
≤1 mg/L
>2 mg/L
1
the S/I-breakpoint was increased from 1.0 to 2.0 to avoid dividing the wild type MIC distribution.
The breakpoints relate to high dose therapy.
2
Strains with MIC values above the S/I 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 sent to a reference laboratory.
3
Non-species related breakpoints have been determined mainly on the basis of
pharmacokinetic/pharmacodynamic 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 are not for
use with species where susceptibility testing is not recommended or for which there is insufficient
evidence that the species in question is a good target (Enterococcus, Neisseria, Gram negative
anaerobes)
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
Staphylococcus aureus* methicillin-susceptible
Coagulase negative meticillin-susceptible
Staphylococcus, including staphylococcus saprophyticus
Streptococci
Aerobic Gram- negative bacteria
Eikenella corrodens
Haemophilus influenzae *
Haemophilus para-influenzae *
Klebsiella oxytoca
Klebsiella pneumoniae *
Legionella pneumophila*
Moraxella catarrhalis *
Pasteurella multocida
Proteus vulgaris
Providencia rettgeri
Anaerobic bacteria
Clostridium perfringens
Fusobacterium
Prevotella($),
Propionibacterium
Other
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Chlamydophila pneumoniae *
Chlamydophila psittaci
Chlamydia trachomatis
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
Staphylococcus coagulase negative methicillin-resistant
Aerobic Gram- negative bacteria
Acinetobacter baumannii *
Citrobacter freundii *
Enterobacter aerogenes
Enterobacter agglomerans
Enterobacter cloacae *
Escherichia coli *
Morganella morganii *
Proteus mirabilis *
Providencia stuartii
Pseudomonas aeruginosa*
Serratia marcescens *
Anaerobic bacteria
Peptostreptococcus
Naturally resistant species
Aerobic Gram-positive bacteria
Enterococcus faecium
Aerobic Gram-negative bacteria
Burkholderia cepacia
Anaerobic bacteria
Bacteroides
Clostridium difficile
* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical
indications.
$ natural intermediate susceptibility
Other information
Nosocomial infections due to P. aeruginosa may require combination therapy.
5.2
Pharmacokinetic properties
Absorption
Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma
concentrations being obtained within 1 h. The absolute bioavailability is approximately 100 %. Food
has little effect on the absorption of levofloxacin.
Distribution
Approximately 30 - 40 % of levofloxacin is bound to serum protein. 500 mg once daily multiple dosing
with levofloxacin showed negligible accumulation. There is modest but predictable accumulation of
levofloxacin after doses of 500 mg twice daily. Steady-state is achieved within 3 days.
Penetration into tissues and body fluids:
Penetration into Bronchial Mucosa, Epithelial Lining Fluid (ELF)
Maximum levofloxacin concentrations in bronchial mucosa and epithelial lining fluid after 500 mg p.o.
were 8.3 μg/g and 10.8 μg/ml respectively. These were reached approximately one hour after
administration.
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Penetration into Lung Tissue
Maximum levofloxacin concentrations in lung tissue after 500 mg p.o. were approximately 11.3 μg/g
and were reached between 4 and 6 hours after administration. The concentrations in the lungs
consistently exceeded those in plasma.
Penetration into Blister Fluid
Maximum levofloxacin concentrations of about 4.0 and 6.7 μg/ml in the blister fluid were reached 2 - 4
hours after administration following 3 days dosing at 500 mg once or twice daily, respectively.
Penetration into Cerebro-Spinal Fluid
Levofloxacin has poor penetration into cerebro-spinal fluid.
Penetration into prostatic tissue
After administration of oral 500mg levofloxacin once a day for three days, the mean concentrations in
prostatic tissue were 8.7 µg/g, 8.2 µg/g and 2.0 µg/g respectively after 2 hours, 6 hours and 24 hours;
the mean prostate/plasma concentration ratio was 1.84.
Concentration in urine
The mean urine concentrations 8 - 12 hours after a single oral dose of 150 mg, 300 mg or 500 mg
levofloxacin were 44 mg/L, 91 mg/L and 200 mg/L, respectively.
Biotransformation
Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and
levofloxacin N-oxide. These metabolites account for < 5 % of the dose excreted in urine. Levofloxacin
is stereochemically stable and does not undergo chiral inversion.
Elimination
Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from
the plasma (t½: 6 - 8 h). Excretion is primarily by the renal route > 85 % of the administered dose).
There are no major differences in the pharmacokinetics of levofloxacin following intravenous and oral
administration, suggesting that the oral and intravenous routes are interchangeable.
Linearity
Levofloxacin obeys linear pharmacokinetics over a range of 50 to 600 mg.
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin 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:
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 levofloxacin 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
levofloxacin pharmacokinetics. There is no evidence that these gender differences are of clinical
relevance.
5.3
Preclinical safety data
During repeat-dose studies, common observations included reduced food consumption and minor
alterations in haematological and biochemical parameters at 200 mg/kg/day in the rat and reduced body
weight, salivation, diarrhoea and decreased urinary pH at 100 mg/kg/day in the monkey.
Levofloxacin had no effect on fertility or reproductive performance and was not teratogenic in the rat.
In the rabbit, levofloxacin had no effect on fertility, was not teratogenic and its only effect on fetuses
was delayed maturation at doses resulting in maternal toxicity.
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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Levofloxacin induced chromosome aberrations in Chinese hamster lung cells in vitro at or above
100 μg/ml, in the absence of metabolic activation. However, levofloxacin did not show any genotoxic
potential in a series of other in vitro and in vivo tests and no indication of carcinogenic potential was
observed.
Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have phototoxic
activity only at very high doses. Levofloxacin did not show any genotoxic potential in a
photomutagenicity assay and it reduced tumour development in a photocarcinogenicity assay.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and
cavities) in rats and dogs. These findings were more marked in young animals. Repeated oral
administration of levofloxacin at 100 mg/kg for 7 days induced focal necrosis and superficial erosion
of the articular cartilage. Single oral administration at 900 mg/kg levofloxacin induced lesions in the
muscle, fascia, tendon sheath, synovial membrane and articular cartilage in the fore- and hind-limbs.
At doses of 300 mg/kg or higher, lesions of the Achilles tendon were noted in the rat.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Tablet core:
Povidone
Crospovidone (Type-B)
Cellulose microcrystalline
Magnesium stearate
Silica colloidal anhydrous
Tablet coating:
Hypromellose E5 Talc
Titanium dioxide (E171)
Macrogol 400
Yellow ferric oxide (E172)
Red ferric oxide (E172)
6.2
Incompatibilities
Not applicable
6.3
Shelf life
3 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Tablets are packed in PVC/aluminium blisters.
For 250 mg, the tablets are provided in pack sizes of 1, 2, 3, 5, 7, 10, 30, 50 and 200 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7
MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited
Sage House, 319, Pinner Road,
North Harrow, Middlesex,
HA1 4 HF,
United Kingdom
8
MARKETING AUTHORISATION NUMBER(S)
PL 20075/0297
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/06/2011
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10
UK/H/4331/001-2/DC
DATE OF REVISION OF THE TEXT
02/06/2011
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1
NAME OF THE MEDICINAL PRODUCT
Levofloxacin 500 mg Film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film coated tablet contains 500 mg of levofloxacin as active substance corresponding to 512.46
mg of levofloxacin hemihydrate.
For a full list of excipients, see section 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet
For 500 mg tablets: Pink coloured, capsule shaped, biconvex, film coated tablet with break line on both
sides. Debossed ‘L’ and ‘V’ either side of the break line on one face.
The tablets can be divided into equal halves.
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
In adults with infections of mild or moderate severity, Levofloxacin Tablets are indicated for the
treatment of the following infections when due to levofloxacin-susceptible microorganisms: (see
section 5.1)
Acute sinusitis (adequately diagnosed according to national and/or local guidelines on the treatment of
respiratory tract infections, and when it is considered inappropriate to use antibacterial agents that are
commonly recommended for the initial treatment of this infection or when these have failed to resolve
the infection),
Acute exacerbations of chronic bronchitis (adequately diagnosed according to national and/or local
guidelines on the treatment of respiratory tract infections, and when it is considered inappropriate to
use antibacterial agents that are commonly recommended for the initial treatment of this infection or
when these have failed to resolve the infection),
Community-acquired pneumonia (when it is considered inappropriate to use antibacterial agents that
are commonly recommended for the initial treatment of this infection),
For 250mg only: Uncomplicated urinary tract infections
Complicated urinary tract infections (including pyelonephritis)
Chronic bacterial prostatitis.
Skin and soft tissue infections.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2
Posology and method of administration
Levofloxacin Tablets are administered once or twice daily. The dosage depends on the type and
severity of the infection and the sensitivity of the presumed causative pathogen.
Treatment time
The duration of therapy varies according to the course of the disease (see table below). As with
antibiotic therapy in general, administration of Levofloxacin Tablets should be continued for a
minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication
has been obtained.
Method of administration
Levofloxacin Tablets should be swallowed whole and with sufficient amount of liquid. The tablets may
be taken during meals or between meals. Levofloxacin Tablets should be taken at least two hours
before iron salts, antacids and sucralfate administration since reduction of absorption can occur (see
section 4.5).
The following dose recommendations can be given for Levofloxacin Tablets:
Dosage in patients with normal renal function
(creatinine clearance > 50 ml/min)
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
Indication
Acute sinusitis
Acute exacerbations of chronic
bronchitis
Community-acquired pneumonia
Uncomplicated urinary tract
infections
Complicated urinary tract infections
including pyelonephritis
Chronic bacterial prostatitis
Skin and soft tissue infections
UK/H/4331/001-2/DC
Daily dose regimen (according
to severity)
500 mg once daily
Duration of
treatment
10 - 14 days
250 to 500 mg once daily
7 - 10 days
500 mg once or twice daily
7 - 14 days
250 mg once daily
3 days
250 mg once daily1
7 - 10 days
500 mg once daily
250 mg once daily or 500 mg
once or twice daily2
28 days
7 - 14 days
1,2
Consideration should be given to increasing the dose in cases of severe infection and special
attention should be paid to available information on resistance to levofloxacin before commencing
therapy.
1
Because of the increasing E.coli resistance the dose 500 mg/day should be considered.
2
Because of the increasing Staphylococcus resistance the dose 500 mg twice daily should be
considered.
Special Populations
Impaired renal function (creatinine clearance ≤ 50 ml/min)
Creatinine clearance
Dosage regimen
250 mg/24 h
First dose: 250 mg
Then:125 mg/24h
Then: 125 mg/48 h
500 mg/24 h
First dose: 500 mg
Then: 250 mg/24 h
Then: 125 mg/24 h
500 mg/12 h
First dose: 500 mg
Then:250 mg/12 h
Then:125 mg/12 h
50-20 ml/min
19-10 ml/min
< 10 ml/min (including
haemodialysis and
Then: 125 mg/48 h
Then: 125 mg/24 h
Then:125 mg/24 h
CAPD)1
1
No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis
(CAPD).
Impaired liver function
No adjustment of dosage is required since levofloxacin is not metabolised to any relevant extent by the
liver and is mainly excreted by the kidneys.
Dosage in elderly
No adjustment of dosage is required in the elderly, other than that imposed by consideration of renal
function (see section 4.4 QT interval prolongation).
In children
Levofloxacin is contraindicated in children and growing adolescents (less than 18 years of age) (see
section 4.3).
4.3
Contraindications
Levofloxacin Tablets must not be used:
in patients hypersensitive to levofloxacin or other quinolones or any of the excipients,
in patients with epilepsy,
in patients with history of tendon disorders related to fluoroquinolone administration,
in children or growing adolescents (up to age of 18)
during pregnancy,
in breast-feeding women.
4.4
Special warnings and precautions for use
In the most severe cases of pneumococcal pneumonia Levofloxacin Tablets may not be the optimal
therapy.
Nosocomial infections due to P. aeruginosa may require combination therapy.
Methicillin-resistant Staphylococcus aureus (MRSA)
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Levofloxacin is not effective against infections caused by MRSA (see section 5.1). In infections
suspicious for MRSA levofloxacin should be combined with an agent approved to treat MRSA
infections.
Tendinitis and tendon rupture
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon
rupture. The risk of tendinitis and tendon rupture is increased in the elderly and in patients using
corticosteroids. Close monitoring of these patients is therefore necessary if they are prescribed
Levofloxacin Tablets. All patients should consult their physician if they experience symptoms of
tendinitis. If tendinitis is suspected, treatment with Levofloxacin Tablets must be halted immediately,
and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.
Clostridium difficile-associated disease
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Levofloxacin
Tablets, may be symptomatic of Clostridium difficile-associated disease, the most severe form of which
is pseudomembranous enterocolitis. If pseudomembranous enterocolitis is suspected, Levofloxacin
Tablets must be stopped immediately and patients should be treated with supportive measures and
specific therapy without delay (e.g. oral metronidazole or vancomycin). Products inhibiting the
peristalsis are contraindicated in this clinical situation.
Patients predisposed to seizures
Levofloxacin Tablets are contraindicated in patients with a history of epilepsy and, as with other
quinolones, should be used with extreme caution in patients predisposed to seizures, such as patients
with pre-existing central nervous system damage; concomitant treatment with fenbufen and similar
non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such
as theophylline (see section 4.5). In case of convulsive seizures, treatment with levofloxacin 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, and so levofloxacin should be
used with caution.
Patients with renal impairment
Since levofloxacin is excreted mainly by the kidneys, the dose of Levofloxacin Tablets should be
adjusted in patients with renal impairment. (see section 4.2).
Hypersensitivity reactions
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema 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.
Hypoglycemia
As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving
concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with insulin. In these
diabetic patients, careful monitoring of blood glucose is recommended. (see section 4.8).
Prevention of photosensitisation
Although photosensitisation is very rare with levofloxacin, it is recommended that patients should not
expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp,
solarium), 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
levofloxacin 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 levofloxacin. In
very rare cases these have progressed to suicidal thoughts and self-endangering behaviour- sometimes
after only a single dose of levofloxacin (see section 4.8). In the event that the patient develops these
reactions, levofloxacin should be discontinued and appropriate measures instituted. Caution is
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recommended if levofloxacin is to be used in psychotic patients or in patients with a history of
psychiatric disease.
Cardiac disorders
Caution should be taken when using fluoroquinolones, including levofloxacin, 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).
- uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)
- elderly
- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
(see section 4.2 Elderly, section 4.5, section 4.8, section 4.9).
Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving
fluoroquinolones, including levofloxacin, which can be rapid in its onset. Levofloxacin should be
discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of
an irreversible condition.
Opiates
In patients treated with levofloxacin, determination of opiates in urine may give false-positive results.
It may be necessary to confirm positive opiate screens by a more specific method.
Hepatobiliary disorders
Cases of hepatic necrosis up to life threatening hepatic failure have been reported with levofloxacin,
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.
4.5
Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on levofloxacin
Iron salts, magnesium- or aluminium-containing antacids
Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminiumcontaining antacids are administered concomitantly. It is recommended that preparations containing
divalent or trivalent cations such as iron salts, or magnesium- or aluminium-containing antacids should
not be taken 2 hours before or after Levofloxacin Tablets administration (see section 4.2). No
interaction was found with calcium carbonate.
Sucralfate
The bioavailability of Levofloxacin Tablets is significantly reduced when administered together with
sucralfate. If the patient is to receive both sucralfate and Levofloxacin Tablets, it is best to administer
sucralfate 2 hours after the Levofloxacin Tablets administration (see section 4.2).
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions of levofloxacin 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.
Levofloxacin 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 levofloxacin. The
renal clearance of levofloxacin was reduced by cimetidine (24 %) and probenecid (34 %). This is
because both drugs are capable of blocking the renal tubular secretion of levofloxacin. 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 levofloxacin is coadministered with drugs that effect the tubular
renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
Effect of levofloxacin on other medicinal products
Ciclosporin
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The half-life of ciclosporin was increased by 33 % when coadministered with levofloxacin.
Vitamin K antagonists
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in
patients treated with levofloxacin 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 the QT interval
Levofloxacin, 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, antipsychotic). (See section 4.4 ).
Other forms of interactions
Meals
There is no clinically relevant interaction with food. Levofloxacin Tablets may therefore be
administered regardless of food intake.
Other relevant information
Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected
to any clinically relevant extent when levofloxacin was administered together with the following drugs:
calcium carbonate
digoxin
glibenclamide
ranitidine.
4.6
Pregnancy and lactation
Pregnancy
There are no data with respect to the use of levofloxacin in pregnant women. Animal studies do not
indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). In
juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been
observed; thus, it cannot be excluded that the drug could cause damage to articular cartilage in the
human immature organism / fetus (see section 5.3). The product is therefore contraindicated during
pregnancy.
Lactation
There is insufficient information with respect to the excretion of levofloxacin in human and/or animal
milk. In the absence of these data and given the potential risk of articular damage, levofloxacin is
contraindicated during breast-feeding.
4.7
Effects on ability to drive and use machines
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).
4.8
Undesirable effects
The information given below is based on data from clinical studies in more than 5000 patients and on
extensive post marketing experience.
The adverse reactions are described according to the MedDRA system organ class below.
Frequencies are defined using the following convention: very common (≥ 1/10), common (≥ 1/100, <
1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known
(cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Cardiac disorders
Rare: Tachycardia
Not Known: ventricular arrhythmia and torsades de pointes (reported predominantly in patients with
risk factors for QT prolongation), Electrocardiogram QT prolonged (see section 4.4 and section 4.9)
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Blood and lymphatic system disorders
Uncommon : Leukopenia, eosinophilia
Rare : Thrombocytopenia, neutropenia
Very rare : Agranulocytosis
Not Known : Pancytopenia, haemolytic anaemia
Nervous system disorders
Uncommon : Dizziness, headache, somnolence
Rare : Convulsion, tremor, paraesthesia,
Very rare: sensory or sensorimotor peripheral neuropathy, dysgeusia including ageusia, parosmia
including anosmia
Eye disorders
Very rare: Visual disturbance
Ear and Labyrinth disorders
Uncommon: Vertigo
Very rare: Hearing impaired
Not known: Tinnitus
Respiratory, thoracic and mediastinal disorders
Rare: Bronchospasm, dyspnoea
Very rare: Pneumonitis allergic
Gastrointestinal disorders
Common: Diarrhoea, nausea
Uncommon: Vomiting, abdominal pain, dyspepsia, flatulence, constipation
Rare: Diarrhoea –haemorrhagic which in very rare cases may be indicative of enterocolitis, including
pseudomembranous colitis
Renal and urinary disorders
Uncommon: Blood creatinine increased
Very rare: Renal failure acute (e.g. due to nephritis interstitial)
Skin and subcutaneous tissue disorders
Uncommon: Rash, pruritus
Rare: Urticaria
Very rare: Angioneurotic oedema, photosensitivity reaction
Not Known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme,
hyperhidrosis
Mucocutaneous reactions may sometimes occur even after the first dose
Musculoskeletal and Connective tissue disorders
Rare: Tendon disorder (see section 4.4) including tendinitis (e.g. Achilles tendon), arthralgia, myalgia
Very rare: Tendon rupture (see section 4.4). This undesirable effect may occur within 48 hours of
starting treatment and may be bilateral, muscular weakness which may be of special importance in
patients with myasthenia gravis
Not Known: Rhabdomyolysis
Metabolism and nutrition disorders
Uncommon: Anorexia
Very rare: Hypoglycemia, particularly in diabetic patients (see section 4.4)
Infections and infestations
Uncommon: Fungal infection (and proliferation of other resistant microorganisms)
Vascular disorders
Rare: Hypotension
General disorders and administration site conditions
Uncommon: Asthenia
Very rare: Pyrexia
Not known: Pain (including pain in back, chest, and extremities)
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Immune system disorders
Very rare: Anaphylactic shock (see section 4.4)
Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose
Not known: Hypersensitivity (see section 4.4)
Hepatobiliary disorders
Common: Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)
Uncommon: Blood bilirubin increased
Very rare: Hepatitis
Not known: Jaundice and severe liver injury, including cases with acute liver failure, have been
reported with levofloxacin, primarily in patients with severe underlying diseases (see section 4.4).
Psychiatric disorders
Uncommon: Insomnia, nervousness
Rare: Psychotic disorder, Depression, confusional state, agitation, anxiety
Very rare: Psychotic reactions with self-endangering behaviour including suicidal ideation or acts (see
section 4.4), hallucination
Other undesirable effects which have been associated with fluoroquinolone administration include:
extrapyramidal symptoms and other disorders of muscular coordination,
hypersensitivity vasculitis,
attacks of porphyria in patients with porphyria.
4.9
Overdose
According to toxicity studies in animals or clinical pharmacology studies performed with supratherapeutic doses, the most important signs to be expected following acute overdosage of levofloxacin
are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and
convulsive seizures, increases in QT interval as well as gastro-intestinal reactions such as nausea and
mucosal erosions.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be
undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection
of gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in
removing levofloxacin from the body. No specific antidote exists.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Anti-infective for systemic use – Antibacterials for systemic use –
Quinolone antibasterials – Fluoroquinolones
ATC code: J01MA12
Levofloxacin 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, levofloxacin acts on the DNA-DNA-gyrase complex and
topoisomerase IV.
PK/PD releationship
The degree of the bactericidal activity of levofloxacin 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(s) of resistance
The main mechanism of resistance is due to a gyr-A mutation. In vitro there is a cross-resistance
between levofloxacin and other fluoroquinolones.
Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other
classes of antibacterial agents.
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Breakpoints
The EUCAST recommended MIC breakpoints for levofloxacin, 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 levofloxacin (2006-06-20):
Pathogen
Susceptible
Resistant
Enterobacteriacae
≤1 mg/L
>2 mg/L
Pseudomonas spp.
≤1 mg/L
>2 mg/L
Acinetobacter spp.
≤1 mg/L
>2 mg/L
Staphylococcus spp.
≤1 mg/L
>2 mg/L
S.pneumoniae 1
≤2 mg/L
>2 mg/L
Streptococcus A,B,C,G
≤1 mg/L
>2 mg/L
H.influenzae M.catarrhalis 2
≤1 mg/L
>1 mg/L
Non-species related breakpoints 3
≤1 mg/L
>2 mg/L
1
the S/I-breakpoint was increased from 1.0 to 2.0 to avoid dividing the wild type MIC distribution.
The breakpoints relate to high dose therapy.
2
Strains with MIC values above the S/I 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 sent to a reference laboratory.
3
Non-species related breakpoints have been determined mainly on the basis of
pharmacokinetic/pharmacodynamic 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 are not for
use with species where susceptibility testing is not recommended or for which there is insufficient
evidence that the species in question is a good target (Enterococcus, Neisseria, Gram negative
anaerobes)
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
Staphylococcus aureus* methicillin-susceptible
Coagulase negative meticillin-susceptible
Staphylococcus, including staphylococcus saprophyticus
Streptococci
Aerobic Gram- negative bacteria
Eikenella corrodens
Haemophilus influenzae *
Haemophilus para-influenzae *
Klebsiella oxytoca
Klebsiella pneumoniae *
Legionella pneumophila*
Moraxella catarrhalis *
Pasteurella multocida
Proteus vulgaris
Providencia rettgeri
Anaerobic bacteria
Clostridium perfringens
Fusobacterium
Prevotella($),
Propionibacterium
Other
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Chlamydophila pneumoniae *
Chlamydophila psittaci
Chlamydia trachomatis
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
Staphylococcus coagulase negative methicillin-resistant
Aerobic Gram- negative bacteria
Acinetobacter baumannii *
Citrobacter freundii *
Enterobacter aerogenes
Enterobacter agglomerans
Enterobacter cloacae *
Escherichia coli *
Morganella morganii *
Proteus mirabilis *
Providencia stuartii
Pseudomonas aeruginosa*
Serratia marcescens *
Anaerobic bacteria
Peptostreptococcus
Naturally resistant species
Aerobic Gram-positive bacteria
Enterococcus faecium
Aerobic Gram-negative bacteria
Burkholderia cepacia
Anaerobic bacteria
Bacteroides
Clostridium difficile
* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical
indications.
$ natural intermediate susceptibility
Other information
Nosocomial infections due to P. aeruginosa may require combination therapy.
5.2
Pharmacokinetic properties
Absorption
Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma
concentrations being obtained within 1 h. The absolute bioavailability is approximately 100 %. Food
has little effect on the absorption of levofloxacin.
Distribution
Approximately 30 - 40 % of levofloxacin is bound to serum protein. 500 mg once daily multiple dosing
with levofloxacin showed negligible accumulation. There is modest but predictable accumulation of
levofloxacin after doses of 500 mg twice daily. Steady-state is achieved within 3 days.
Penetration into tissues and body fluids:
Penetration into Bronchial Mucosa, Epithelial Lining Fluid (ELF)
Maximum levofloxacin concentrations in bronchial mucosa and epithelial lining fluid after 500 mg p.o.
were 8.3 μg/g and 10.8 μg/ml respectively. These were reached approximately one hour after
administration.
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Penetration into Lung Tissue
Maximum levofloxacin concentrations in lung tissue after 500 mg p.o. were approximately 11.3 μg/g
and were reached between 4 and 6 hours after administration. The concentrations in the lungs
consistently exceeded those in plasma.
Penetration into Blister Fluid
Maximum levofloxacin concentrations of about 4.0 and 6.7 μg/ml in the blister fluid were reached 2 - 4
hours after administration following 3 days dosing at 500 mg once or twice daily, respectively.
Penetration into Cerebro-Spinal Fluid
Levofloxacin has poor penetration into cerebro-spinal fluid.
Penetration into prostatic tissue
After administration of oral 500mg levofloxacin once a day for three days, the mean concentrations in
prostatic tissue were 8.7 µg/g, 8.2 µg/g and 2.0 µg/g respectively after 2 hours, 6 hours and 24 hours;
the mean prostate/plasma concentration ratio was 1.84.
Concentration in urine
The mean urine concentrations 8 - 12 hours after a single oral dose of 150 mg, 300 mg or 500 mg
levofloxacin were 44 mg/L, 91 mg/L and 200 mg/L, respectively.
Biotransformation
Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and
levofloxacin N-oxide. These metabolites account for < 5 % of the dose excreted in urine. Levofloxacin
is stereochemically stable and does not undergo chiral inversion.
Elimination
Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from
the plasma (t½: 6 - 8 h). Excretion is primarily by the renal route > 85 % of the administered dose).
There are no major differences in the pharmacokinetics of levofloxacin following intravenous and oral
administration, suggesting that the oral and intravenous routes are interchangeable.
Linearity
Levofloxacin obeys linear pharmacokinetics over a range of 50 to 600 mg.
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin 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:
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 levofloxacin 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
levofloxacin pharmacokinetics. There is no evidence that these gender differences are of clinical
relevance.
5.3
Preclinical safety data
During repeat-dose studies, common observations included reduced food consumption and minor
alterations in haematological and biochemical parameters at 200 mg/kg/day in the rat and reduced body
weight, salivation, diarrhoea and decreased urinary pH at 100 mg/kg/day in the monkey.
Levofloxacin had no effect on fertility or reproductive performance and was not teratogenic in the rat.
In the rabbit, levofloxacin had no effect on fertility, was not teratogenic and its only effect on fetuses
was delayed maturation at doses resulting in maternal toxicity.
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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Levofloxacin induced chromosome aberrations in Chinese hamster lung cells in vitro at or above 100
μg/ml, in the absence of metabolic activation. However, levofloxacin did not show any genotoxic
potential in a series of other in vitro and in vivo tests and no indication of carcinogenic potential was
observed.
Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have phototoxic
activity only at very high doses. Levofloxacin did not show any genotoxic potential in a
photomutagenicity assay and it reduced tumour development in a photocarcinogenicity assay.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and
cavities) in rats and dogs. These findings were more marked in young animals. Repeated oral
administration of levofloxacin at 100 mg/kg for 7 days induced focal necrosis and superficial erosion
of the articular cartilage. Single oral administration at 900 mg/kg levofloxacin induced lesions in the
muscle, fascia, tendon sheath, synovial membrane and articular cartilage in the fore- and hind-limbs.
At doses of 300 mg/kg or higher, lesions of the Achilles tendon were noted in the rat.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Tablet core:
Povidone
Crospovidone (Type-B)
Cellulose microcrystalline
Magnesium stearate
Silica colloidal anhydrous
Tablet coating:
Hypromellose E5 Talc
Titanium dioxide (E171)
Macrogol 400
Yellow ferric oxide (E172)
Red ferric oxide (E172)
6.2
Incompatibilities
Not applicable
6.3
Shelf life
3 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Tablets are packed in PVC/aluminium blisters.
For 500 mg, the tablets are provided in pack sizes of 1, 2, 5, 7, 10, 30, 50, 200 and 500 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7
MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited
Sage House, 319, Pinner Road,
North Harrow, Middlesex,
HA1 4 HF,
United Kingdom
8
MARKETING AUTHORISATION NUMBER(S)
PL 20075/0298
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/06/2011
10
DATE OF REVISION OF THE TEXT
02/06/2011
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Module 3
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Module 4
Labelling
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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Module 5
Scientific discussion during initial procedure
I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Reference Member State
(RMS) and Concerned Member States (CMSs) consider that the applications for
Levofloxacin 250 and 500mg Film-coated Tablets could be approved for treatment of the
following infections caused by levofloxacin susceptible microorganisms.
● Acute sinusitis (adequately diagnosed according to national and/or local
guidelines on the treatment of respiratory tract infections, and when it is
considered inappropriate to use antibacterial agents that are commonly
recommended for the initial treatment of this infection or when these have failed
to resolve the infection),
● Acute exacerbations of chronic bronchitis (adequately diagnosed according to
national and/or local guidelines on the treatment of respiratory tract infections,
and when it is considered inappropriate to use antibacterial agents that are
commonly recommended for the initial treatment of this infection or when these
have failed to resolve the infection),
● Community-acquired pneumonia (when it is considered inappropriate to use
antibacterial agents that are commonly recommended for the initial treatment of
this infection),
●
For 250mg only: Uncomplicated urinary tract infections
●
Complicated urinary tract infections (including pyelonephritis)
●
Chronic bacterial prostatitis.
●
Skin and soft tissue infections.
Consideration should be given to official guidance on the appropriate use of antibacterial
agents.
These applications were submitted under Article 10.1 with applicant claiming that
Levofloxacin 250 and 500mg Film-coated Tablets are generic medicinal products of Tavanic
250mg and 500mg Tablets (PL 13402/0011-2), which were first licensed to Hoechst Marion
Roussel Ltd, UK, on 6th June 1997.
With the UK as the RMS in these Decentralised Procedures (UK/H/4331/01-2/DC), Accord
Healthcare Limited applied for the Marketing Authorisations for Levofloxacin 250 and
500mg Film-coated Tablets in Belgium, Bulgaria, Germany, Greece, Spain, France, Hungary,
Italy, Portugal and Romania
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-)
enantiomer of the racemic drug substance ofloxacin. As a fluoroquinolone antibacterial
agent, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.
No new preclinical and clinical studies were conducted, which is acceptable given that the
applications were based on being generic medicinal products of originator products that have
been licensed for over 10 years. A bioequivalence study was carried out in accordance with
Good Clinical Practice (GCP).
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP)
are in place for these product types at all sites responsible for the manufacture and assembly
of these products. For manufacturing sites outside the Community, the RMS has accepted
copies of current GMP certificates of satisfactory inspection summary reports issued by the
inspection services of the competent authorities as certification that acceptable standards of
GMP are in place at those non-Community sites.
The RMS considers that the Pharmacovigilance System as described by the applicant fulfils
the requirements and provides adequate evidence that the applicant has the services of a
Qualified Person responsible for pharmacovigilance and has the necessary means for the
notification of any adverse reaction suspected of occurring either in the Community or in a
third country. A suitable justification has been provided for non-submission of a Risk
Management Plan.
All Member States agreed to grant respective licence for the above products at the end of
procedure (Day 210 – 11th May 2011). After a subsequent national phase, the UK granted a
licence for these products on 2nd June 2011 (PL 20075/0297-8).
36
PAR Levofloxacin 250 and 500 mg Film-coated Tablets
II.
UK/H/4331/001-2/DC
ABOUT THE PRODUCT
Name of the product in the Reference
Member State
Name(s) of the active substance(s)
(INN)
Pharmacotherapeutic classification
(ATC code)
Pharmaceutical form and strength(s)
Reference numbers for the
Decentralised Procedure
Reference Member State
Concerned Member States
Marketing Authorisation Number(s)
Name and address of the
authorisation holder
Levofloxacin 250 and 500mg Film-coated
Tablets
Levofloxacin hemihydrate
J01MA12
Film-coated Tablets, 250mg and 500mg
UK/H/4331/001-2/DC
United Kingdom
Belgium, Bulgaria, Germany, Greece, Spain,
France, Hungary, Italy, Portugal and Romania
PL 20075/0297-8
Accord Healthcare Limited
Sage House, 319, Pinner Road,
North Harrow, Middlesex,
HA1 4 HF,
United Kingdom
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
UK/H/4331/001-2/DC
III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
DRUG SUBSTANCE
INN:
Levofloxacin hemihydrate
Chemical Name: (-)-(s)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7oxo-7H-pyrido[1,2,3-de]-1,4 benzoxazine-6-carboxylic acid hemihydrate.
Structure:
Molecular Formula: C18H20FN3O4.½ H2O
Molecular Weight: 370.38 g / mol
Appearance: a light yellowish-white to yellowish-white crystalline powder with no odour. It is freely
soluble in glacial acetic acid and chloroform, sparingly soluble in water, acetone and methanol and
slightly soluble in ethyl acetate and ethanol.
Synthesis of the drug substance from the designated starting material has been adequately
described and appropriate in-process controls and intermediate specifications are applied.
Satisfactory specification tests are in place for all starting materials and reagents, and these
are supported by relevant Certificates of Analysis. Appropriate proof-of-structure data have
been supplied. All potential known impurities have been identified and characterised.
An appropriate specification is provided for the drug substance. Analytical methods have
been appropriately validated and are satisfactory for ensuring compliance with the relevant
specifications. Certificates of Analysis for all working standards have been provided.
Batch analysis data are provided and comply with the proposed specification.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging
used to store the drug substance. Confirmation has been provided that the primary packaging
complies with current guidelines concerning materials in contact with food.
Appropriate stability data have been generated, supporting a suitable retest period when the
drug substance is stored in the packaging proposed.
DRUG PRODUCT
Other Ingredients
Other ingredients consist of the pharmaceutical excipients povidone, crospovidone (Type-B),
cellulose microcrystalline, magnesium stearate and silica colloidal anhydrous making up the
tablet core; and hypromellose E5 talc, titanium dioxide (E171), macrogol 400, yellow ferric
oxide (E172) and red ferric oxide (E172) making up the tablet coating.
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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All excipients comply with their respective European Pharmacopoeia monographs with the
exception of yellow ferric oxide (E172) and red ferric oxide (E172) which comply with an inhouse specification. Satisfactory Certificates of Analysis have been provided for all
excipients.
It had been confirmed that the excipients used are free of TSE/BSE and the corresponding
certificates issued by each supplier were provided. This is acceptable.
Pharmaceutical Development
The objective of the development programme was to formulate robust, stable tablets that
contain the same active ingredient as Tavanic 250 and 500mg Tablets.
Comparative impurity and dissolution profiles have been presented for test and reference
products.
Manufacture
A satisfactory batch formula has been provided for the manufacture of the product, along
with an appropriate account of the manufacturing process. The manufacturing process has
been validated and has shown satisfactory results. Process validation data on commercial
batches have been provided. The results are satisfactory.
Finished Product Specification
The finished product specification is satisfactory. Test methods have been described and
adequately validated. Batch data have been provided and comply with the specification.
Certificates of Analysis have been provided for any working standards used.
Container-Closure System
The finished product is packed in PVC/aluminium blisters. The pack sizes are,
250mg
1, 2, 3, 5, 7, 10, 30, 50 and 200 tablets.
500 mg
1, 2, 5, 7, 10, 30, 50, 200 and 500 tablets.
Specifications and Certificates of Analysis for all packaging materials have been provided.
These are satisfactory. All primary packaging complies with EU legislation regarding contact
with food.
Stability
Finished product stability studies have been conducted in accordance with current guidelines
and in the packaging proposed for marketing.
Based on the results, a shelf-life of 3 years with no special storage conditions are set. This is
satisfactory.
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and
Labelling
The SmPC, PIL and labels are pharmaceutically acceptable.
A package leaflet has been submitted to the MHRA along with results of consultations with
target patient groups ("user testing"), in accordance with Article 59 of Council Directive
2001/83/EC. The results indicate that the package leaflet is well-structured and organised,
easy to understand and written in a comprehensive manner. The test shows that the
patients/users are able to act upon the information that it contains.
The proposed artwork complies with the relevant statutory requirements. In line with current
legislation the applicant has also included the name of the product in Braille on the outer
packaging and has included sufficient space for a standard UK pharmacy dispensing label.
The Marketing Authorisation Holder has stated that not all licensed pack sizes may be
marketed. They have committed to submitting mock-ups for unmarketed pack sizes to the
relevant regulatory authorities for approval before those packs are commercially marketed.
Marketing Authorisation Application (MAA) Forms
The MAA forms are pharmaceutically satisfactory.
Expert report
The pharmaceutical expert report has been written by an appropriately qualified person and is
a suitable summary of the pharmaceutical aspects of the dossier.
Conclusion
There are no objections to the approval of these products from a pharmaceutical point of
view.
III.2 PRE-CLINICAL ASPECTS
The pharmacological, pharmacokinetic and toxicological properties of levofloxacin
hemihydrate are well-known.
No new preclinical data have been supplied with these applications and none are required for
applications of this type. The pre-clinical expert report has been written by an appropriately
qualified person and is a suitable summary of the pre-clinical aspects of the dossier.
A suitable justification has been provided for non-submission of environmental risk
assessment.
There are no objections to the approval of these products from a preclinical point of view.
III.3 CLINICAL ASPECTS
Clinical Pharmacology
Pharmacokinetics
In support of these applications, the marketing authorisation holder has submitted the
following bioequivalence study:
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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This is an open label, single dose, balanced, randomised, two-treatment, two-period,
crossover comparative bioavailability study of Levofloxacin 500mg film-coated tablets (test)
and Tavanic 500mg Tablets (reference) in healthy, adult male subjects under fasting
conditions.
Serial blood samples were collected in each period at pre-dose and at 0.25, 0.5, 0.75, 1, 1.25,
1.5, 1.75, 2, 2.25, 2.5, 2.75, 3.5, 4.5, 6, 8, 12, 16, 20, 24, 30, 36, 42 and 48 hours following
the drug administration in each period. The washout period was 12 days.
Results
Table 1.
Bioequivalence results for Ln-transformed test/reference ratios with
90% Confidence Intervals
Parameters
Test
Reference
T/R ratio
90% CI (%)
(%)
Cmax (ng/mL)
6.072
5.715
106.2
97.09-116.27
51.618
50.912
101.4
99.63-103.18
AUCt (ng.h/mL)
AUC∞ (ng.h/mL)
53.005
52.204
101.5
99.84-103.26
The 90% confidence intervals for Cmax and AUC were within the pre-defined limits (80125%). Bioequivalence has been shown for the test formulation (Levofloxacin 500 mg filmcoated tablets) and the reference formulation (Tavanic 500mg Tablets). A biowaiver has been
granted to the 250mg tablet based on the studies conducted in line with the requirements of
the Committee for Proprietary Medicinal Products Notes for Guidance on “Guideline on the
Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98 Rev.1 Corr**).
Pharmacodynamics
No new data have been submitted and none are required for these generic applications.
Clinical Efficacy
No new data have been submitted and none are required for these generic applications.
Clinical Safety
No new data have been submitted and none are required for these generic applications.
Expert Report
A clinical overall summary, written by an appropriately qualified physician, has been
provided. This is a satisfactory, non-critical summary of Module 5.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and
labelling
The SmPCs, PIL and labelling are medically satisfactory and consistent with those for the
reference products.
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Clinical Expert Report
The clinical expert report is written by an appropriately qualified physician and is a suitable
summary of the clinical aspects of the dossier.
Marketing Authorisation Application (MAA) Forms
The MAA forms are medically satisfactory.
Clinical Conclusion
There are no objections to the approval of these products from a clinical point of view.
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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IV.
OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
QUALITY
The important quality characteristics of Levofloxacin 250 and 500mg Film-coated Tablets
are well-defined and controlled. The specifications and batch analytical results indicate
consistency from batch to batch. There are no outstanding quality issues that would have a
negative impact on the benefit/risk balance.
PRECLINICAL
No new preclinical data were submitted and none are required for applications of these type.
EFFICACY
Bioequivalence have been demonstrated between the applicant’s Levofloxacin 500mg Filmcoated Tablets and the reference product, Tavanic 500mg Tablets and the results can be
extrapolated to the 250mg Film-coated Tablets.
No new or unexpected safety concerns arise from these applications.
The SmPC and PIL are satisfactory and consistent with those of the reference products.
Satisfactory labelling has also been submitted.
RISK-BENEFIT ASSESSMENT
The quality of the product is acceptable and no new preclinical or clinical safety concerns
have been identified. Extensive clinical experience with levofloxacin hemihydrate is
considered to have demonstrated the therapeutic value of the compound. The risk-benefit is,
therefore, considered to be positive.
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PAR Levofloxacin 250 and 500 mg Film-coated Tablets
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Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted
Application
type
Scope
Outcome
44