Update to PL due to outcome of art. 31 referral procedure from the EMA

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.

Section 4.4 -wording in the section has changed slightly as per the below, crossed out text has been removed and bold text has been added

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 of clinical manifestations of severe hypersensitivity reactions moxifloxacin should be discontinued and suitable treatment (e.g. treatment for shock) initiated.

Peripheral neuropathy

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).

Section 4.8
Vasculitis has been added as a very rare side effect.

Avelox Infusion (glass bottles) – 1410/27/3
www.medicines.ie

(Inserted Text; Deleted Text)

4.4          Special warnings and precautions for use

…

Dysglycemia

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with moxifloxacin. 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. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).

…  

4.8          Undesirable effects

…

…

10.          DATE OF REVISION OF THE TEXT

December 2014 June 2015

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

1 bottle of 250 ml contains 400 mg moxifloxacin (as hydrochloride).

1 ml contains 1.6 mg moxifloxacin (as hydrochloride).

Excipient with known effect: 250 ml of solution for infusion contains 787 mg (34 mmol) sodium.

For the full list of excipients, see section 6.1.

3.       PHARMACEUTICAL FORM

Solution for infusion

250 ml glass bottle or 250 ml polyolefine flexible bag filled with minimum 250 ml cClear, yellow solution.

4.6     Fertility, pregnancy and lactation

Breast-feeding

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).

4.8       Undesirable effects

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Quinolone antibacterials, fluoroquinolones, ATC code: J01MA14

Mode Mechanism of action

Moxifloxacin inhibits bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) that are required for bacterial DNA replication, transcription and repair.

6.1     List of excipients

Sodium chloride

Hydrochloric acid 1 N (for pH-adjustment)

Sodium hydroxide solution 2 N (for pH-adjustment)

Water for injections

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 04 April 2003

Date of last renewal: 30 November 201308

10.     DATE OF REVISION OF THE TEXT

03/2012December 2014

……………………

Excipient with known effect: 250 ml of solution for infusion contains 34 mmol sodium.

For a the full list of excipients, see section 6.1.

3.            PHARMACEUTICAL FORM

Solution for infusion

250 ml glass bottle filled with minimum 250 ml cClear, yellow solution.

4.2          Posology and method of administration

Posology

The recommended dose is 400 mg moxifloxacin, infused once daily.

……………………………..

Renal/hepatic impairment

No adjustment of dosage is required in patients with mild to severely impaired renal function or in patients on chronic dialysis i.e. haemodialysis and continuous ambulatory peritoneal dialysis (see section 5.2 for more details).

There is insufficient data in patients with impaired liver function (see section 4.3).

Other special populations

No adjustment of dosage is required in the elderly and in patients with low bodyweight.

Children and adolescents Paediatric population

Moxifloxacin is contraindicated in children and growing adolescents. Efficacy and safety of moxifloxacin in children and adolescents have not been established (see section 4.3).

4.3          Contraindications

-               Hypersensitivity to moxifloxacin, other quinolones or to any of the excipients listed in section 6.1.

4.4          Special warnings and precautions for use

………………………………

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.
…………………………………..

Hypersensitivity/allergic reactions

………………………………….

Peripheral neuropathy

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 (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 endangering behaviour such as suicide attempts (see section 4.8)……………………

……………………………….

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.

4.5          Interaction with other medicinal products and other forms of interaction

…………………………

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.

………………………….

In vitro studies with human cytochrome P450 enzymes supported these findings. Considering these results a metabolic interaction via cytochrome P450 enzymes is unlikely.

…………………………

4.6          Fertility, pPregnancy and lactation

……………………………..

Lactation Breastfeeding

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).

Fertility

Animal studies do not indicate impairment of fertility (see section 5.3).

4.8          Undesirable effects

Adverse reactions observed in clinical trials 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 (³ 1/100 to < 1/10)

-               uncommon (³ 1/1,000 to < 1/100)

-               rare (³ 1/10,000 to < 1/1,000)

-               very rare (< 1/10,000)

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: hypernatraemia, hypercalcaemia, haemolytic anaemia, rhabdomyolysis, photosensitivity reactions, peripheral neuropathy (see section 4.4).

5.1          Pharmacodynamic properties

…………………………………….

Breakpoints

EUCAST clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2012) (31.01.2006):

…………………………………

5.2          Pharmacokinetic properties

…………………

Metabolism Biotransformation

………………………

Renal impairment

The pharmacokinetic properties of moxifloxacin are not significantly different in patients with renal impairment (including creatinine clearance > 20 ml/min/1.73 m²). As renal function decreases, concentrations of the M2 metabolite (glucuronide) increase by up to a factor of 2.5 (with a creatinine clearance of < 30 ml/min/1.73 m²).

Hepatic impairment

On the basis of the pharmacokinetic studies carried out so far in patients with liver failure (Child Pugh A, B), it is not possible to determine whether there are any differences compared with healthy volunteers. Impaired liver function was associated with higher exposure to M1 in plasma, whereas exposure to parent drug was comparable to exposure in healthy volunteers. There is insufficient experience in the clinical use of moxifloxacin in patients with impaired liver function.

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 bottle and in multipacks containing 5 bottles (5 packs of 1 bottles).

Not all pack sizes may be marketed.

10.          DATE OF REVISION OF THE TEXT

{Deleted text; Inserted text}

4.3       Contraindications

-               Hypersensitivity to moxifloxacin, other quinolones or to any of the excipients.

-               Pregnancy and lactation (see section 4.6).

-               Children and growing adolescents Patients below 18 years of age.

-               Patients with a history of tendon disease/disorder related to quinolone treatment.

………………………

4.4       Special warnings and precautions for use

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

………………………………………………

Tendon inflammation, tendon rupture

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 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 (see sections 4.3 and 4.8). Tendon inflammation and rupture may occur even up to several months after discontinuing quinolone therapy including moxifloxacin.

…………………………………………………..

4.5          Interaction with other medicinal products and other forms of interaction

Interactions with medicinal products

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)

-           tricyclic antidepressive agents

-           certain antimicrobial agents (saquinavir, 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.

……………………………………………………………..

The Date of Revision of the text (Section 10) has been updated to “February 2012”

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

“Interactions with medicinal products

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)

-        tricyclic antidepressive agents

-        certain antimicrobial agents (sparfloxacin, erythromycin IV, pentamidine, antimalarials particularly halofantrine)

-        certain antihistaminics (terfenadine, astemizole, mizolastine)

-        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”.

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

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:

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.”

10.     DATE OF REVISION OF THE TEXT

February 2011

10. DATE of REVISION of text

changed to “August 2010”

Addition of the following to section 4.4:

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).

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:

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

Section 7

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.