When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Section 4.5 (Interaction with other medicinal products and other forms of interaction): has been updated as follows:
BEFORE:
“Interactions with medicinal products
An additive effect on QT interval 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):
- antiarrhythmics class IA (e.g. quinidine, hydroquinidine, disopyramide)
- antiarrhythmics class III (e.g. amiodarone, sotalol, dofetilide, ibutilide)
- neuroleptics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sultopride)
- tricyclic antidepressive agents
- certain antimicrobial agents (sparfloxacin, erythromycin IV, pentamidine, antimalarials particularly halofantrine)
- certain antihistaminics (terfenadine, astemizole, mizolastine)
- others (cisapride, vincamine IV, bepridil, diphemanil).
Moxifloxacin should be used with caution in patients who are taking medication that can reduce potassium levels or medication that is associated with clinically significant bradycardia.”
AFTER
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):
- anti-arrhythmics class IA (e.g. quinidine, hydroquinidine, disopyramide)
- anti-arrhythmics class III (e.g. amiodarone, sotalol, dofetilide, ibutilide)
- antipsychotics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sultopride)
- others (cisapride, vincamine IV, bepridil, diphemanil).” Section 4.9 (overdose): has been updated as follows: BEFORE: “No specific countermeasures after accidental overdose are recommended. General symptomatic therapy should be initiated. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Concomitant administration of charcoal with a dose of 400 mg oral or intravenous moxifloxacin will reduce systemic availability of the drug by more than 80% or 20% respectively. The use of charcoal early during absorption may be useful to prevent excessive increase in the systemic exposure to moxifloxacin in cases of oral overdose.” AFTER: “No specific countermeasures after accidental overdose are recommended. In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Concomitant administration of charcoal with a dose of 400 mg oral or intravenous moxifloxacin will reduce systemic availability of the drug by more than 80% or 20% respectively. The use of charcoal early during absorption may be useful to prevent excessive increase in the systemic exposure to moxifloxacin in cases of oral overdose.” In Section 10, the date of revision of the text has been changed from “March 2011” to “July 2011”.
Section 4.9 (overdose): has been updated as follows:
“No specific countermeasures after accidental overdose are recommended. General symptomatic therapy should be initiated. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Concomitant administration of charcoal with a dose of 400 mg oral or intravenous moxifloxacin will reduce systemic availability of the drug by more than 80% or 20% respectively. The use of charcoal early during absorption may be useful to prevent excessive increase in the systemic exposure to moxifloxacin in cases of oral overdose.”
AFTER:
“No specific countermeasures after accidental overdose are recommended. In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Concomitant administration of charcoal with a dose of 400 mg oral or intravenous moxifloxacin will reduce systemic availability of the drug by more than 80% or 20% respectively. The use of charcoal early during absorption may be useful to prevent excessive increase in the systemic exposure to moxifloxacin in cases of oral overdose.”
In Section 10, the date of revision of the text has been changed from “March 2011” to “July 2011”.
6.4 Special precautions for storage
Do not refrigerate or freeze. Do not store below 15°C.
6.5 Nature and contents of container
Colourless glass bottles (type 2) with a chlorobutyl or bromobutyl rubber stopper as closure. The 250 ml bottle is available in packs of 1 and 5 bottles.
6.6 Special precautions for disposal and other handling
At cool storage temperatures precipitation may occur, which will re-dissolve at room temperature. It is therefore recommended not to store the infusion solution in a refrigerator below 15°C.
10. DATE OF REVISION OF THE TEXT
March 2011
Significant changes to section 4.4
4.4 Special warnings and precautions for use
Retired text
Newly approved
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 medication that can reduce potassium levels. See also section 4.3. 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.
- 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.
- 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 these cases 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 which may predispose to seizures or lower the seizure threshold.
- Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias, or weakness have been reported in patients receiving quinolones. 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 (see section 4.8).
- 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.
- 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.
- Moxifloxacin should be used with caution in patients with myasthenia gravis because the symptoms can be exacerbated.
- Tendon inflammation and rupture may occur with quinolone therapy including moxifloxacin, particularly in elderly patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue treatment with moxifloxacin and rest the affected limb(s).
- 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.
- 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).
- 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.
- Clinical efficacy of moxifloxacin in the treatment of severe burn infections, fasciitis, major abscesses and diabetic foot infections with osteomyelitis has not been established.
- This medicinal product contains 787 mg (approximately 34 mmol) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.
- Moxifloxacin therapy may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth causing false negative results.
- 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).
Prolongation of QTc interval and potentially QTc-prolongation-related clinical conditions
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 section 4.3. 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 / 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 these cases 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.
Serious bullous skin reactions
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.
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.
Peripheral neuropathy
Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias, or weakness have been reported in patients receiving quinolones. 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 (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-endangering 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.
Tendon inflammation, tendon rupture
Tendon inflammation and rupture may occur with quinolone therapy including moxifloxacin, particularly 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. Tendon inflammation and rupture may occur even up to several months after discontinuing quinolone therapy including moxifloxacin.
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).
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.
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 moxifloxacin in the treatment of severe burn infections, fasciitis, major abscesses and diabetic foot infections with osteomyelitis has not been established.
Patients on sodium diet
This medicinal product contains 787 mg (approximately 34 mmol) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.
Interference with biological tests
Moxifloxacin therapy may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth causing false negative results.
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).
4.5 Interaction with other medicinal products and other forms of interaction
Subheading: “Interactions with medicinal products”
An additive effect on QT interval of between moxifloxacin and other medicinal products that may prolong the QTc interval cannot be excluded.
Subheading: “Changes in INR”
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.
4.8 Undesirable effects
Insertion of System organ class to table:
System Organ Class
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
Vascular disorders
Vasodilatation
Hypertension
Hypotension
Addition of “muscle weakness” under organ class “Musculoskeletal, connective tissue and bone disorders” as a rare undesirable effect.
4.9 Overdose
Insertion of: “ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.”
February 2011
10. DATE of REVISION of text
changed to “August 2010”
Addition of the following to section 4.4:
Section 4.7
Addition of “acute transient loss of vision” as an example of a potential CNS reaction.
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).
Section 4.8
Addition of “Agranulocytosis” as a very rare adverse event observed.
In psychiatric disorders addition of “suicidal ideations/ thoughts, or suicide attempts” as example of self endangering behaviour under the category very rare adverse event observed.
Under eye disorders addition of “Transient loss of vision (especially in the course of CNS reactions, see sections 4.4 and 4.7)” as a very rarely observed adverse event.
Under ear and labyrinth disorders insertion of “Hearing impairment incl. deafness (usually reversible)” as a rarely observed adverse event.
Addition of “haemolytic anaemia” and “peripheral neuropathy” as side effects reported with other fluoroquinolones.
Section 7
“Bayer Healthcare AG” changed to “Bayer Schering Pharma AG”
Section 10
Changed to “May 2010”
Section 4.4:
Cases of fulminant hepatitis potentially leading to life-threatening liver failure 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.
'Pseudomembranous colitis has been reported in association with the use of broad spectrum antibiotics including moxifloxacin' has been replaced with the following text:
Antibiotic associated colitis (incl. pseudomembranous colitis) has been reported in association with the use of broad spectrum antibiotics including moxifloxacin.
Section 4.8:
Headers and text updated to read as follows:
≤ 1/10,000
Blood and Lymphatic System Disorders
Anaemia
Leucopenia(s)
Neutropenia
Thrombocytopenia
Thrombocythemia
Blood eosinophilia
Prothrombin time prolonged / INR increased
Prothrombin level increased / INR decreased
Psychiatric Disorders
Anxiety reactions
Psychomotor hyperactivity / agitation
Emotional lability
Depression (in very rare cases potentially culminating in self-endangering behaviour)
Hallucination
Depersonalization
Psychotic reactions (potentially culminating in self-endangering behaviour)
Cardiac and Vascular Disorders
QT prolongation in patients with hypokalaemia (see section 4.4)
QT prolongation (see section 4.4)
Palpitations
Tachycardia
Atrial fibrillation
Angina pectoris
Ventricular tachyarrhythmias
Syncope
Unspecified arrhythmias
Torsade de Pointes (see section 4.4)
Cardiac arrest (see section 4.4)
Gastrointestinal Disorders
Nausea
Vomiting
Gastrointestinal and abdominal pains
Diarrhoea
Anorexia
Constipation
Dyspepsia
Flatulence
Gastritis
Increased amylase
Dysphagia
Stomatitis
Antibiotic associated colitis (incl. pseudomembranous colitis, in very rare cases associated with life-threatening complications, see section 4.4)
Hepatobiliary Disorders
Increase in transaminases
Hepatic impairment (incl. LDH increase)
Increased bilirubin
Increased gamma-glutamyl-transferase
Increase in blood alkaline phosphatase
Jaundice
Hepatitis (predominantly cholestatic)
Fulminant hepatitis potentially leading to life-threatening liver failure (see section 4.4)
Skin and Subcutaneous Tissue Disorders
Pruritus
Rash
Urticaria
Dry skin
Bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening)
General Disorders and Administration Site Conditions
Injection and infusion site reactions
Feeling unwell (predominantly asthenia or fatigue)
Painful conditions (incl. pain in back, chest, pelvic and extremities)
Sweating
Infusion site (thrombo-) phlebitis
Oedema
Uncommon: Ventricular tachyarrhythmias, hypotension, oedema, antibiotic associated colitis (incl. pseudomembranous colitis, in very rare cases associated with life-threatening complications, see section 4.4).
In vitro Susceptibility Data
Clinical and Laboratory Standards Institute¢â (CLSI) MIC and disc diffusion breakpoints for Staphylococcus spp. and fastidious organisms (M100-S17, 2007) and MIC breakpoints for anaerobes (M11-A7, 2007). (Aerobes M100-S16,2006 has been deleted).
Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
Enterococcus faecalis*
Staphylococcus aureus (methicillin-resistant)+
Aerobic Gram-negative micro-organisms
Enterobacter cloacae
Escherichia coli*
Klebsiella oxytoca
MA holder is now Bayer Limited, The Atrium, Blackthorn Avenue, Dublin 18.
Section 4.4 (Special warnings and precautions for use:
Bullet point 2, paragraph 3 has been re-worded.
Bullet point 9, has been reworded.
Bullet point 10, has been reworded
Section 4.5 (Interaction with other medicinal products and other forms of interactions):
Paragraph 7 has been amended to read: “Clinical studies have shown that there are no interactions following …..”.
Section 4.7 (Effects on ability to drive and use machines):
The wording has been amended slightly: “….. (e.g. dizziness, see section 4.8).
Section 4.8 (Undesirable effects):
The table has been extensively revised to reflect MedDRA terminology.
Section 5.1 (Pharmacodynamic properties):
The wording has been updated in line with the Company Core Data Sheet.
Section 10 (Date of revision of the text):
This has been updated to ’26.07.2006’.
Avelox 400 mg solution for infusion is indicated for the treatment of:
· Community acquired pneumonia
· Complicated skin and skin structure infections (see section 4.4)
caused by bacteria susceptible to moxifloxacin in patients requiring initial parenteral therapy.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.