Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

The use of moxifloxacin 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 moxifloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).

The benefit of moxifloxacin treatment especially in infections with a low degree of severity should be balanced with the information contained in the warnings and precautions section.

Prolongation of QTc interval and potentially QTc-prolongation-related clinical conditions 

IV:
Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram in some patients. The magnitude of QT prolongation may increase with increasing plasma concentrations due to rapid intravenous infusion. Therefore, the duration of infusion should not be less than the recommended 60 minutes and the intravenous dose of 400 mg once a day should not be exceeded. For more details see below and refer to sections 4.3 and 4.5.

Treatment with moxifloxacin should be stopped if signs or symptoms that may be associated with cardiac arrhythmia occur during treatment, with or without ECG findings.
Moxifloxacin should be used with caution in patients with any condition pre-disposing to cardiac arrhythmias (e.g.
acute myocardial ischaemia) because they may have an increased risk of developing ventricular arrhythmias (incl.
torsade de pointes) and cardiac arrest. See also sections 4.3 and 4.5.
Moxifloxacin should be used with caution in patients who are taking medications that can reduce potassium levels. See also sections 4.3 and 4.5.
Moxifloxacin should be used with caution in patients who are taking medications associated with clinically significant bradycardia. See also section 4.3.
Female patients and elderly patients may be more sensitive to the effects of QTc-prolonging medications such as moxifloxacin and therefore special caution is required.


Tablets:
Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram in some patients. In the analysis of ECGs obtained in the clinical trial program, QTc prolongation with moxifloxacin was 6 msec ± 26 msec, 1.4% compared to baseline. As women tend to have a longer baseline QTc interval compared with men, they may be more sensitive to QTc-prolonging medications. Elderly patients may also be more susceptible to drug-associated effects on the QT interval.
Medication that can reduce potassium levels should be used with caution in patients receiving moxifloxacin (see also sections 4.3 and 4.5).
Moxifloxacin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients), such as acute myocardial ischaemia or QT prolongation as this may lead to an increased risk for ventricular arrhythmias (incl. torsade de pointes) and cardiac arrest (see also section 4.3).
The magnitude of QT prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose should not be exceeded.
If signs of cardiac arrhythmia occur during treatment with moxifloxacin, treatment should be stopped and an ECG should be performed.

Hypersensitivity/allergic reactions
Hypersensitivity and allergic reactions have been reported for fluoroquinolones including moxifloxacin after first administration. Anaphylactic reactions can progress to a life-threatening shock, even after the first administration. In cases of clinical manifestations of severe hypersensitivity reactions moxifloxacin should be discontinued and suitable treatment (e.g. treatment for shock) initiated.

Severe liver disorders
Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported with moxifloxacin (see section 4.8). Patients should be advised to contact their doctor prior to continuing treatment if signs and symptoms of fulminant hepatic disease develop such as rapidly developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy.
Liver function tests/investigations should be performed in cases where indications of liver dysfunction occur.

Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome), Stevens Johnson syndrome (SJS), Acute Generalised Exanthematous Pustulosis (AGEP) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), which could be life- threatening or fatal, have been reported with moxifloxacin (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, moxifloxacin should be discontinued immediately, and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS, TEN, AGEP or DRESS with the use of moxifloxacin, treatment with moxifloxacin must not be restarted in this patient at any time.


Patients predisposed to seizures
Quinolones are known to trigger seizures. Use should be with caution in patients with CNS disorders or in the presence of other risk factors which may predispose to seizures or lower the seizure threshold. In case of seizures, treatment with moxifloxacin should be discontinued and appropriate measures instituted.

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. Moxifloxacin 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.

Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysaesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with moxifloxacin 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).

Psychiatric reactions
Psychiatric reactions may occur even after the first administration of quinolones, including moxifloxacin. In very rare cases depression or psychotic reactions have progressed to suicidal thoughts and self-injurious behaviour such as suicide attempts (see section 4.8). In the event that the patient develops these reactions, moxifloxacin should be discontinued, and appropriate measures instituted. Caution is recommended if moxifloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.


Antibiotic-associated diarrhoea incl. colitis
Antibiotic-associated diarrhoea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, has been reported in association with the use of broad spectrum antibiotics including moxifloxacin and may range in severity from mild diarrhoea to fatal colitis.
Therefore it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of moxifloxacin. If AAD or AAC is suspected or confirmed, ongoing treatment with antibacterial agents, including moxifloxacin, should be discontinued and adequate therapeutic measures should be initiated immediately. Furthermore, appropriate infection control measures should be undertaken to reduce the risk of transmission. Drugs inhibiting peristalsis are contraindicated in patients who develop serious diarrhoea.

Patients with myasthenia gravis
Moxifloxacin should be used with caution in patients with myasthenia gravis because the symptoms can be exacerbated.

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 (see sections 4.3 and 4.8). The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, 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 moxifloxacin 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.
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 , Behceet´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.


Patients with renal impairment
Elderly patients with renal disorders should use moxifloxacin with caution if they are unable to maintain adequate fluid intake, because dehydration may increase the risk of renal failure.

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).

Dysglycemia
As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with moxifloxacin (see section 4.8). In moxifloxacin-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g.
sulfonylurea) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.


Prevention of photosensitivity reactions
Quinolones have been shown to cause photosensitivity reactions in patients. However, studies have shown that moxifloxacin has a lower risk to induce photosensitivity. Nevertheless patients should be advised to avoid exposure to either UV irradiation or extensive and/or strong sunlight during treatment with moxifloxacin (see section 4.8).

Patients with glucose-6-phosphate dehydrogenase deficiency
Patients with a family history of or actual glucose-6-phosphate dehydrogenase deficiency are prone to haemolytic reactions when treated with quinolones. Therefore, moxifloxacin should be used with caution in these patients.
Peri-arterial tissue inflammation
Moxifloxacin solution for infusion is for intravenous administration only. Intra-arterial administration should be avoided since preclinical studies demonstrated peri-arterial tissue inflammation following infusion by this route.


Patients with special cSSSI
Clinical efficacy of intravenous moxifloxacin in the treatment of severe burn infections, fasciitis and diabetic foot infections with osteomyelitis has not been established.

Interference with biological tests
Moxifloxacin therapy may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth causing false negative results in samples taken from patients currently receiving moxifloxacin.
Patients with MRSA infections
Moxifloxacin is not recommended for the treatment of MRSA infections. In case of a suspected or confirmed infection due to MRSA, treatment with an appropriate antibacterial agent should be started (see section 5.1).

Paediatric population
Due to adverse effects on the cartilage in juvenile animals (see section 5.3) the use of moxifloxacin in children and adolescents < 18 years is contraindicated (see section 4.3).

Information about excipients

IV:
This medicinal product contains 787 mg (approximately 34 mmol) sodium per bottle with 250 ml solution for infusion, equivalent to 39.35 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.


Tablets:
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially “sodium-free”.

Effects on Driving

4.7 Effects on ability to drive and use machines
No studies on the effects of moxifloxacin on the ability to drive and use machines have been performed.
However, fluoroquinolones including moxifloxacin may result in an impairment of the patient's ability to drive or operate machinery due to CNS reactions (e.g. dizziness; acute, transient loss of vision, see section 4.8) or acute and short lasting loss of consciousness (syncope, see section 4.8). Patients should be advised to see how they react to moxifloxacin before driving or operating machinery.