4.1. Therapeutic indications

Because of the risk of prolonged, disabling and potentially irreversible serious adverse drug reactions (see section 4.4 and section 4.8) this product must only be prescribed when other antibiotics that are commonly recommended for the infection are inappropriate. This applies to all indications listed below. Situations where other antibiotics are considered to be inappropriate are where:

• there is resistance to other first-line antibiotics recommended for the infection;

• other first-line antibiotics are contraindicated in an individual patient;

• other first-line antibiotics have caused side effects requiring treatment to be stopped

• treatment with other first-line antibiotics has failed.

Levofloxacin Ibigen solution for infusion is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1):

• Community-acquired pneumonia

• Complicated skin and soft tissue infections

• Acute pyelonephritis and complicated urinary tract infections (see section 4.4)

• Chronic bacterial prostatitis

• Inhalation Anthrax: post exposure prophylaxis and curative treatment (see section 4.4)

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

The dosage depends on the type and severity of the infection and the susceptibility of the presumed causative pathogen. Treatment with Levofloxacin Ibigen after initial use of the intravenous preparation may be completed with an appropriate oral presentation according to the SPC of an appropriate oral presentation and as considered appropriate for the individual patient. Given the bioequivalence of the parenteral and oral forms, the same dosage can be used.

The following dose recommendations can be given for Levofloxacin Ibigen:

Dose in patients with normal renal function (creatinine clearance> 50 ml/min)

Indication

Daily dose regimen

(according to severity)

Duration of treatment1

(according to severity)

Community-acquired pneumonia

500 mg once or twice daily

7-14 days

Pyelonephritis

500 mg once daily

7-10 days

Complicated urinary tract infections

500 mg once daily

7-14 days

Chronic bacterial prostatitis

500mg once daily

28 days

Complicated skin and soft tissue infections

500 mg once or twice daily

7-14 days

Inhalation anthrax

500 mg once daily

8 weeks

1Treatment duration includes intravenous plus oral treatment. The time to switch from intravenous to oral treatment depends on the clinical situation but is normally 2 to 4 days

Special populations

Impaired renal function (creatinine clearance 50ml/min)

Dose regimen

250 mg/24 h

500 mg/24 h

500 mg/12 h

Creatinine clearance

first dose: 250 mg

first dose: 500 mg

first dose: 500 mg

50 - 20 ml/min

then: 125 mg/24 h

then: 250 mg/24 h

then: 250 mg/12 h

19-10 ml/min

then: 125 mg/48 h

then: 125 mg/24 h

then: 125 mg/12 h

< 10 ml/min (including haemodialysis and CAPD) 1

then: 125 mg/48 h

then: 125 mg/24 h

then: 125 mg/24 h

1No 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.

Elderly population

No adjustment of dosage is required in the elderly, other than that imposed by consideration of renal function (See section 4.4 “Tendinitis and tendon rupture” and “QT interval prolongation”).

Paediatric population

Levofloxacin Ibigen is contraindicated in children and growing adolescents (see section 4.3).

Method of administration

Levofloxacin Ibigen solution for infusion is administered by slow intravenous infusion once or twice daily. The infusion time must be at least 30 minutes for 250 mg or 60 minutes for 500 mg Levofloxacin Ibigen solution for infusion (see section 4.4).

For incompatibilities see section 6.2 and compatibility with other infusion solutions see section 6.6.

4.3. Contraindications

Levofloxacin Ibigen solution for infusion must not be used:

• in patients hypersensitive to levofloxacin or any other quinolone or to any of the excipients listed in section 6.1

• in patients with epilepsy

• in patients with history of tendon disorders related to fluoroquinolone administration

• in children or growing adolescents

• during pregnancy

• in breast-feeding women

4.4. Special warnings and precautions for use

Prolonged, disabling and potentially irreversible serious adverse drug reactions

Cases of prolonged (continuing for months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (including musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. 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, so that symptoms can be appropriately investigated and to avoid further exposure which could potentially worsen adverse reactions.

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).

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).

Resistance to fluoroquinolones of E. coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.

Inhalation Anthrax: use in humans is based on in vitro Bacillus anthracis susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.

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 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.

Infusion Time

The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for 500mg Levofloxacin Ibigen solution for infusion should be observed. It is known, for ofloxacin, that during infusion tachycardia and a temporary decrease in blood pressure may develop. In rare cases, as a consequence of a profound drop in blood pressure, circulatory collapse may occur. Should a conspicuous drop in blood pressure occur during infusion of levofloxacin, (l-isomer of ofloxacin) the infusion must be halted immediately.

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, patients receiving daily doses of 1000 mg levofloxacin and those treated concurrently with corticosteroids. 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 (see sections 4.3 and 4.8).

Myoclonus

Cases of myoclonus have been reported in patients receiving levofloxacin (see section 4.8). The risk of myoclonus is increased in older patients, and in patients with renal impairment if the dose of levofloxacin is not adjusted as per the creatinine clearance. Levofloxacin should be discontinued immediately at the first occurrence of myoclonus and appropriate treatment should be initiated.

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 is contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or concomitant treatment with active substances 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 Levofloxacin Ibigen 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 hyperglycaemia have been reported (see section 4.8), usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.

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 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 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 anti-arrhythmics, 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, 4.9).

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypoesthesia, 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. Post marketing 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 result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Blood disorders

Bone marrow failure including leukopenia, neutropenia, pancytopenia, haemolytic anaemia, thrombocytopenia, aplastic anaemia, or agranulocytosis may develop during treatment with levofloxacin (see section 4.8). If any of these blood disorders is suspected, blood counts should be monitored. In case of abnormal results, discontinuation of treatment with levofloxacin should be considered.

Interference with laboratory test

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.

Important information about excipients

This medicinal product contains 177 mg sodium per 50 ml and 354 mg per 100 ml, equivalent to 8.85% and 17.7% respectively of the WHO recommended maximum daily intake of 2g sodium for an adult.

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

Effect of other medicinal products on Levofloxacin Ibigen

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 Levofloxacin Ibigen 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 anti-arrhythmics, 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.

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 Ibigen must not be used in pregnant women (see sections 4.3 and 5.3).

Breast-feeding

Levofloxacin Ibigen 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 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 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

Levofloxacin Ibigen has some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) which 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 as follows:

very common (≥1/10),

common (≥1/100, <1/10),

uncommon (≥1/1000, <1/100),

rare (≥1/10000, <1/1000),

very rare (<1/10000),

not known (cannot be estimated from the available data).

In the following table, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

MedDRA

System organ class

Frequency

Undesirable Effects

Infections and infestations

Uncommon

Fungal infection including Candida infection, Pathogen resistance

Blood and lymphatic system disorders

Uncommon

Leukopenia, Eosinophilia

Rare

Thrombocytopenia, Neutropenia

Not known

Bone marrow failure including aplastic anaemia, pancytopenia, agranulocytosis, haemolytic anaemia

Immune system disorders

Rare

Angioedema, Hypersensitivity (see section 4.4)

Not known

Anaphylactic shocka, Anaphylactoid shocka , (see section 4.4)

Metabolism and nutritional disorders

Uncommon

Anorexia

Rare

Hypoglycaemia particularly in diabetic patients (see section 4.4)

Not known

Hyperglycaemia, Hypoglycaemic coma (see section 4.4)

Psychiatric disorders*

Common

Insomnia

Uncommon

Anxiety, Confusional state, Nervousness

Rare

Psychotic reactions (with e.g. hallucination, paranoia), Depression, Agitation, Abnormal dreams, Nightmares

Not known

Psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt (see section 4.4). Mania

Nervous system disorders*

Common

Headache, Dizziness

Uncommon

Somnolence, Tremor, Dysgeusia

Rare

Convulsion (see sections 4.3 and 4.4), Paraesthesia

Not known

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. Myoclonus

Eye disorders*

Rare

Visual disturbances such as blurred vision (see section 4.4)

Not known

Transient vision loss (see section 4.4)

Ear and Labyrinth disorders*

Uncommon

Vertigo

Rare

Tinnitus

Not known

Hearing loss, Hearing impaired

Cardiac disorders**

Rare

Tachycardia, Palpitation

Not known

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**

Common

Phlebitis

Rare

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon

Dyspnoea

Not known

Bronchospasm, Pneumonitis allergic

Gastrointestinal disorders

Common

Diarrhoea, Vomiting, Nausea

Uncommon

Abdominal pain, Dyspepsia, Flatulence, Constipation

Not known

Diarrhoea–haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis (see section 4.4), Pancreatitis

Hepatobiliary disorders

Common

Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)

Uncommon

Blood bilirubin increased

Not known

Jaundice and severe liver injury, including fatal cases with acute liver failure, primarily in patients with severe underlying diseases (see section 4.4), Hepatitis

Skin and subcutaneous tissue disordersb

Uncommon

Rash, Pruritus, Urticaria, Hyperhidrosis

Not known

Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme, Photosensitivity reaction (see section 4.4), Leukocytoclastic vasculitis, Stomatitis, Skin hyperpigmentation

Rare

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section 4.4), Fixed drug eruption

Musculo-skeletal and connective tissue disorders*

Uncommon

Arthralgia, Myalgia

Rare

Tendon disorder (see sections 4.3 and 4.4) including tendinitis and tendon rupture (e.g. Achilles tendon), Muscular weakness which may be of special importance in patients with myasthenia gravis (see section 4.4)

Not known

Rhabdomyolysis, Ligament rupture, Muscle rupture, Arthritis

Renal and urinary disorders

Uncommon

Blood creatinine increased

Rare

Renal failure acute (e.g. due to interstitial nephritis)

General disorders and administration site conditions*

Common

Infusion site reaction (pain, reddening)

Uncommon

Asthenia

Rare

Pyrexia

Not known

Pain (including pain in back, chest, and extremities)

Endocrine disorders

Rare

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

aAnaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.

bMucocutaneous reactions may sometimes occur even after the first dose

* 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, fatigue, psychiatric symptoms, memory impairment 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). A range of psychiatric symptoms may occur as part of these side effects, which may include, but are not necessarily limited to, sleep disorders, anxiety, panic attacks, confusion, or depression. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. The frequency of these prolonged, disabling and potentially irreversible serious drug reactions cannot be estimated with precision using available data, but the reporting incidence from adverse drug reaction reports indicates the frequency is at minimum between 1/1,000 and 1/10,000 (corresponding to the Rare frequency category).

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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

According to toxicity studies in animals or clinical pharmacology studies performed with supra-therapeutic doses, the most important signs to be expected following acute overdosage of Levofloxacin Ibigen solution for infusion are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval.

CNS effects including confusional state, convulsion, myoclonus, hallucination, and tremor have been observed in post marketing experience.

Management

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing levofloxacin from the body. No specific antidote exists.