Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Bayer plc, 400 South Oak Way, Reading RG2 6AD
Both in preclinical investigations and in humans, changes in cardiac electrophysiology have been observed following exposure to moxifloxacin, in the form of QT prolongation. For reasons of drug safety, moxifloxacin is therefore contraindicated in patients with:
Moxifloxacin should not be used concurrently with other drugs that prolong the QT interval (see also section 4.5).
Due to limited clinical data, moxifloxacin is also contraindicated in patients with impaired liver function (Child Pugh C) and in patients with transaminases increase >5fold ULN.
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.
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.
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.
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.
Cases of bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with moxifloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.
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.
Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias, or weakness have been reported in patients receiving quinolones including moxifloxacin. 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 an irreversible condition (see section 4.8).
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 (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.
Moxifloxacin should be used with caution in patients with myasthenia gravis because the symptoms can be exacerbated.
Tendon inflammation and rupture (especially Achilles tendon), sometimes bilateral, may occur with quinolone therapy including moxifloxacin, even within 48 hours of starting treatment and have been reported up to several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue treatment with moxifloxacin, rest the affected limb(s) and consult their doctor immediately in order to initiate appropriate treatment (e.g. immobilisation) for the affected tendon (see sections 4.3 and 4.8).
Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population. Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet ́s disease, hypertension, known atherosclerosis). In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
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.
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.
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.
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.
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.
Clinical efficacy of moxifloxacin in the treatment of severe burn infections, fasciitis and diabetic foot infections with osteomyelitis has not been established.
This medicinal product contains 787 mg (approximately 34 mmol) sodium per bottle with 250ml solution for infusion, equivalent to 39.35% of the WHO recommended maximum daily intake of 2g sodium for an adult.
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.
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).
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).
An additive effect on QT interval prolongation of moxifloxacin and other medicinal products that may prolong the QTc interval cannot be excluded. This might lead to an increased risk of ventricular arrhythmias, including torsade de pointes. Therefore, co-administration of moxifloxacin with any of the following medicinal products is contraindicated (see also section 4.3):
Moxifloxacin should be used with caution in patients who are taking medication that can reduce potassium levels (e.g. loop and thiazide-type diuretics, laxatives and enemas [high doses], corticosteroids, amphotericin B) or medication that is associated with clinically significant bradycardia.
After repeated dosing in healthy volunteers, moxifloxacin increased C max of digoxin by approximately 30% without affecting AUC or trough levels. No precaution is required for use with digoxin.
In studies conducted in diabetic volunteers, concomitant administration of oral moxifloxacin with glibenclamide resulted in a decrease of approximately 21% in the peak plasma concentrations of glibenclamide. The combination of glibenclamide and moxifloxacin could theoretically result in a mild and transient hyperglycaemia. However, the observed pharmacokinetic changes for glibenclamide did not result in changes of the pharmacodynamic parameters (blood glucose, insulin). Therefore no clinically relevant interaction was observed between moxifloxacin and glibenclamide.
A large number of cases showing an increase in oral anticoagulant activity have been reported in patients receiving antibacterial agents, especially fluoroquinolones, macrolides, tetracyclines, cotrimoxazole and some cephalosporins. The infectious and inflammatory conditions, age and general status of the patient appear to be risk factors. Under these circumstances, it is difficult to evaluate whether the infection or the treatment caused the INR (international normalised ratio) disorder. A precautionary measure would be to more frequently monitor the INR. If necessary, the oral anticoagulant dosage should be adjusted as appropriate.
Clinical studies have shown no interactions following concomitant administration of moxifloxacin with: ranitidine, probenecid, oral contraceptives, calcium supplements, morphine administered parenterally, theophylline, cyclosporine or itraconazole.
In vitro studies with human cytochrome P450 enzymes supported these findings. Considering these results a metabolic interaction via cytochrome P450 enzymes is unlikely.
Moxifloxacin has no clinically relevant interaction with food including dairy products.
The safety of moxifloxacin in human pregnancy has not been evaluated. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of immature animals and reversible joint injuries described in children receiving some fluoroquinolones, moxifloxacin must not be used in pregnant women (see section 4.3).
There is no data available in lactating or nursing women. Preclinical data indicate that small amounts of moxifloxacin are secreted in milk. In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of immature animals, breast-feeding is contraindicated during moxifloxacin therapy (see section 4.3).
Animal studies do not indicate impairment of fertility (see section 5.3).
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.
Adverse reactions observed in clinical trials and derived from post-marketing reports with moxifloxacin 400 mg daily administered by the intravenous or oral route (intravenous only, sequential [IV/oral] and oral administration) sorted by frequencies are listed below:
Apart from nausea and diarrhoea all adverse reactions were observed at frequencies below 3%.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: 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).
Common: Superinfections due to resistant bacteria or fungi e.g. oral and vaginal candidiasis
Uncommon: Anaemia, Leucopenia(s), Neutropenia, Thrombocytopenia, Thrombocythemia, Blood eosinophilia, Prothrombin time prolonged/INR increased
Very Rare: Prothrombin level increased/INR decreased, Agranulocytosis
Uncommon: Allergic reaction (see section 4.4)
Rare: Anaphylaxis incl. very rarely life-threatening shock (see section 4.4), Allergic oedema/angiooedema (incl. laryngeal oedema, potentially life-threatening, see section 4.4)
Uncommon: Hyperlipidemia
Rare: Hyperglycemia, Hyperuricemia
Very Rare: Hypoglycemia
Uncommon: Anxiety reactions, Psychomotor hyperactivity/agitation
Rare: Emotional lability, Depression (in very rare cases potentially culminating in self-injurious behaviour, such as suicidal ideations/ thoughts, or suicide attempts, see section 4.4), Hallucination
Very Rare: Depersonalization, Psychotic reactions (potentially culminating in self-injurious behaviour, such as suicidal ideations/thoughts, or suicide attempts, see section 4.4)
Common: Headache, Dizziness
Uncommon: Par- and Dysaesthesia, Taste disorders (incl. ageusia in very rare cases), Confusion and disorientation, Sleep disorders (predominantly insomnia), Tremor, Vertigo, Somnolence
Rare: Hypoaesthesia, Smell disorders (incl. anosmia), Abnormal dreams, Disturbed coordination (incl. gait disturbances, esp. due to dizziness or vertigo), Seizures incl. grand mal convulsions (see section 4.4), Disturbed attention, Speech disorders, Amnesia, Peripheral neuropathy and polyneuropathy
Very Rare: Hyperaesthesia
Uncommon: Visual disturbances incl. diplopia and blurred vision (especially in the course of CNS reactions, see section 4.4)
Rare: Photophobia
Very Rare: Transient loss of vision (especially in the course of CNS reactions, see sections 4.4 and 4.7), Uveitis and bilateral acute iris transillumination (see section 4.4)
Rare: Tinnitus, Hearing impairment incl. deafness (usually reversible)
Common: QT prolongation in patients with hypokalaemia (see sections 4.3 and 4.4)
Uncommon: QT prolongation (see section 4.4), Palpitations, Tachycardia, Atrial fibrillation, Angina pectoris
Rare: Ventricular tachyarrhythmias, Syncope (i.e. acute and short lasting loss of consciousness)
Very Rare: Unspecified arrhythmias, Torsade de Pointes (see section 4.4), Cardiac arrest (see section 4.4)
Uncommon: Vasodilatation
Rare: Hypertension, Hypotension
Very Rare: Vasculitis
Uncommon: Dyspnea (including asthmatic conditions)
Common: Nausea, Vomiting, Gastrointestinal and abdominal pains, Diarrhoea
Uncommon: Decreased appetite and food intake, Constipation, Dyspepsia, Flatulence, Gastritis, Increased amylase
Rare: Dysphagia, Stomatitis, Antibiotic-associated colitis (incl. pseudo-membranous colitis, in very rare cases associated with life-threatening complications, see section 4.4)
Common: Increase in transaminases
Uncommon: Hepatic impairment (incl. LDH increase), Increased bilirubin, Increased gamma-glutamyl-transferase, Increase in blood alkaline phosphatase
Rare: Jaundice, Hepatitis (predominantly cholestatic)
Very Rare: Fulminant hepatitis potentially leading to life-threatening liver failure (incl. fatal cases, see section 4.4)
Uncommon: Pruritus, Rash, Urticaria, Dry skin
Very Rare: Bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening, see section 4.4)
Uncommon: Arthralgia, Myalgia
Rare: Tendonitis (see section 4.4), Muscle cramp, Muscle twitching, Muscle weakness
Very Rare: Tendon rupture (see section 4.4), Arthritis, Muscle rigidity, Exacerbation of symptoms of myasthenia gravis (see section 4.4)
Uncommon: Dehydration
Rare: Renal impairment (incl. increase in BUN and creatinine), Renal failure (see section 4.4)
Common: Injection and infusion site reactions
Uncommon: Feeling unwell (predominantly asthenia or fatigue), Painful conditions (incl. pain in back, chest, pelvic and extremities), Sweating, Infusion site (thrombo-) phlebitis
Rare: Oedema
The following undesirable effects have a higher frequency category in the subgroup of IV treated patients with or without subsequent oral therapy:
Common: Increased gamma-glutamyl-transferase.
Uncommon: Ventricular tachyarrhythmias, hypotension, oedema, antibiotic-associated colitis (incl. pseudomembranous colitis, in very rare cases associated with life-threatening complications, see section 4.4), seizures incl. grand mal convulsions (see section 4.4), hallucination, renal impairment (incl. increase in BUN and creatinine), renal failure (see section 4.4).
There have been very rare cases of the following side effects reported following treatment with other fluoroquinolones, which might possibly also occur during treatment with moxifloxacin: increased intracranial pressure (including pseudotumor cerebri), hypernatraemia, hypercalcaemia, haemolytic anaemia, rhabdomyolysis, photosensitivity reactions (see section 4.4).
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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
The following solutions are incompatible with moxifloxacin solution for infusion:
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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