AMESOL Film-coated tablet Ref.[28104] Active ingredients: Levofloxacin

Source: Υπουργείο Υγείας (CY)  Revision Year: 2020  Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus

4.3. Contraindications

Amesol tablets must not be used:

  • in patients hypersensitive to levofloxacin or other quinolones or 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.

4.4. Special warnings and precautions for use

The use of levofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section 4.8). Treatment of these patients with levofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).

Aortic aneurysm and dissection, and heart valve regurgitation/incompetence

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).

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 congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection or heart valve disease, or in presence of other risk factors or conditions predisposing

  • for both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet’s disease, hypertension, rheumatoid arthritis) or additionally
  • for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome) or additionally
  • for heart valve regurgitation/incompetence (e.g. infective endocarditis).

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin. Therefore levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to levofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).

Levofloxacin may be used in the treatment of Acute Bacterial Sinusitis and Acute Exacerbation of Chronic bronchitis when these infections have been adequately diagnosed.

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 of E. coli to fluoroquinolones.

Inhalation Anthrax: Use in humans in 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.

Prolonged, disabling and potentially irreversible serious adverse drug reactions

Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, those treated concurrently with corticosteroids and in patients receiving daily doses of 1000 mg levofloxacin. Therefore, concomitant use of corticosteroids should be avoided.

At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with levofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin (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 levofloxacin. If CDAD is suspected or confirmed, levofloxacin 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. Levofloxacin iscontraindicated 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 that lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures (see section 4.8), 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. Therefore, if levofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.

Patients with renal impairment

Since levofloxacin is excreted mainly by the kidneys, the dose of Amesol 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 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 cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN: also known as Lyell’s syndrome), Stevens Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with levofloxacin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of levofloxacin, treatment with levofloxacin must not be restarted in this patient at any time.

Dysglycaemia

As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic 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 levofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial 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 levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomittantly (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 recommended if levofloxacin 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 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, antipsychotics)
  • uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)
  • 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 levofloxacin in these populations. (See section 4.2 – Elderly, 4.5, 4.8, and 4.9).

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with levofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition (see section 4.8).

Hepatobiliary disorders

Cases of hepatic necrosis up to fatal 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.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin 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 levofloxacin, especially if prolonged, may results in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Interference with laboratory tests.

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 more specific method.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on Amesol

Iron salts, zinc salts, magnesium- or aluminium-containing antacids, didanosine

Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminium-containing antacids, or didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents) are administered concomitantly with Amesol tablets. Concurrent administration of fluoroquinolones with multi-vitamins containing zinc appears to reduce their oral absorption. It is recommended that preparations containing divalent or trivalent cations such as iron salts, zinc salts or magnesium- or aluminium-containing antacids, or didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents) should not be taken 2 hours before or after levofloxacin tablet administration (see section 4.2). Calcium salts have a minimal effect on the oral absorption of levofloxacin.

Sucralfate

The bioavailability of levofloxacin is significantly reduced when administered together with sucralfate. If the patient is to receive both sucralfate and Amesol, it is best to administer sucralfate 2 hours after the Amesol 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 affect 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 levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.

Effect of Amesol on other medicinal products

Ciclosporin

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 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, antipsychotics). (see section 4.4 QT interval prolongation).

Other relevant information

In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.

Other forms of interactions

Food

There is no clinically relevant interaction with food. Amesol tablets may therefore be administered regardless of food intake.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data from 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). However in the absence of human data and due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in pregnant women. (See sections 4.3 and 5.3)

Breast-feeding

Amesol is contraindicated in breast-feeding women. There is insufficient information on the excretion of levofloxacin in human milk; however other fluoroquinolones are excreted in breast milk. In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in breast-feeding women. (See sections 4.3 and 5.3).

Fertility

Levofloxacin caused no impairment of fertility or reproductive performance in rats.

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 8300 patients and on extensive post marketing experience. Frequencies are defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ classCommon
(≥1/100 to <1/10)
Uncommon
(≥1/1,000 to <1/100)
Rare
(≥1/10,000 to <1/1,000)
Not known
(cannot be
estimated from
available data)
Infections and infestations  Fungal infection
Including Candida infection
Pathogen resistance
  
Blood and lymphatic system disorders  Leukopenia
Eosinophilia
Thrombocytopenia
Neutropenia
Pancytopenia
Agranulocytosis
Haemolytic anaemia
Immune system disorders   Angioedema
Hypersensitivity (see section 4.4)
Anaphylactic shocka
Anaphylactoid shocka (see section 4.4)
Endocrine disorders   Syndrome of
inappropriate
secretion
of antidiuretic
hormone (SIADH)
 
Metabolism and nutrition disorders  AnorexiaHypoglycaemia
particularly in
diabetic patients
(see section 4.4)
Hyperglycaemia
Hypoglycaemic coma
(see section 4.4)
Psychiatric disorders* InsomniaAnxiety
Confusional state
Nervousness
Psychotic
reactions (with
e.g. hallucination,
paranoia)
Depression
Agitation
Abnormal dreams
Nightmares
Psychotic
disorders with
self-endangering behaviour
including suicidal
ideation or suicide
attempt (see section 4.4)
Nervous system disorders* Headache
Dizziness
Somnolence
Tremor
Dysgeusia
Convulsion (see
sections 4.3 and 4.4)
Paraesthesia
Peripheral sensory
neuropathy (see
section 4.4)
Peripheral sensory
motor neuropathy
(see section 4.4)
Parosmia
including anosmia
Dyskinesia
Extrapyramidal
disorder
Ageusia
Syncope
Benign
intracranial
hypertension
Eye disorders*   Visual
disturbances
such as
blurred vision
(see section 4.4)
Transient vision
loss (see section
4.4), uveitis
Ear and Labyrinth disorders*  VertigoTinnitusHearing loss
Hearing impaired
Cardiac disorders**   Tachycardia
Palpitation
Ventricular
tachycardia, which
may result
in cardiac arrest
Ventricular
arrhythmia and
torsade de pointes
(reported predominantly in
patients with
risk factors of
QT prolongation)
Electrocardiogram
QT prolonged
(see sections 4.4
and 4.9)
Vascular disorders** Applies to
iv form only:
Phlebitis
 Hypotension 
Respiratory, thoracic and
mediastinal disorders
 Dyspnoea Bronchospasm,
Pneumonitis
allergic
Gastrointestinal disorders Diarrhoea
Vomiting
Nausea
Abdominal pain
Dyspepsia
Flatulence
Constipation
 Diarrhoea –
haemorrhagic
which in very rare
cases may be
indicative of
enterocolitis,
including
pseudomembranous
colitis (see section 4.4)
Pancreatitis
Hepatobiliary disorders Hepatic enzyme
increased
(ALT/AST,
alkaline
phosphatase,
GGT)
Blood bilirubin
increased
 Jaundice and
severe liver injury,
including cases
with fatal acute
liver failure,
primarily in
patients with
severe underlying
diseases (see
section 4.4)
Hepatitis
Skin and subcutaneous tissue disordersb  Rash
Pruritus
Urticaria
Hyperhidrosis
Drug Reaction
with Eosinophilia
and Systemic
Symptoms
(DRESS) (see
section 4.4), Fixed
drug eruption
Toxic epidermal
necrolysis
Stevens-Johnson
syndrome
Erythema multiforme
Photosensitivity
reaction
(see section 4.4)
Leukocytoclastic
Vasculitis
Stomatitis
Musculoskeletal and connective tissue disorders*  Arthralgia
Myalgia
Tendon disorder
(see sections
4.3 and 4.4) including
tendinitis (e.g.
Achilles tendon)
Muscular
weakness which
may be of
importance in
patients with
myasthenia gravis
(see section 4.4)
Rhabdomyolysis
Tendon rupture
(e.g. Achilles
tendon)
(see sections
4.3 and 4.4)
Ligament rupture
Muscle rupture
Arthritis
Renal and urinary disorders  Blood creatinine
increased
Renal failure
acute (e.g.
due to
Interstitial nephritis)
 
General disorders and administration site conditions* Applies to iv form
only:
Infusion site
reaction (pain,
reddening)
AstheniaPyrexiaPain (including
pain in back
, chest, and
extremities)

a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose
b Mucocutaneous reactions may sometimes occur even after the first dose
* Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see section 4.4).
** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.4).

Other undesirable effects which have been associated with fluoroquinolone administration include:

  • attacks of porphyria in patients with porphyria

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

6.2. Incompatibilities

Not applicable.

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