Consumer medicine information

Moxifloxacin APOTEX

Moxifloxacin

BRAND INFORMATION

Brand name

Moxifloxacin APOTEX

Active ingredient

Moxifloxacin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Moxifloxacin APOTEX.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

This medicine contains the active ingredient moxifloxacin, which is an antibiotic belonging to a group of medicines called quinolones. These antibiotics work by killing the bacteria that are causing your infection.

Moxifloxacin will not work against infections caused by viruses such as colds or the flu.

It is used to treat infections of the lungs, airways and sinuses in adults. In certain infections, you may require treatment with moxifloxacin injection followed by a course of moxifloxacin tablets e.g. severe and complicated skin and skin structure infections.

Even if you have read the Consumer Medicine Information for moxifloxacin injection, you should read this leaflet as well as it contains information specific to the tablets.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

There is no evidence that this medicine is addictive.

This medicine should not be used in children and adolescents under 18 years of age.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • moxifloxacin or other medicines belonging to the quinolone family (e.g. ciprofloxacin, norfloxacin or nalidixic acid)
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you have or have had any of the following medical conditions:

  • a condition called "QTc prolongation", which is a type of abnormal heart rhythm
  • blood tests that show lower than normal potassium levels

Do not take this medicine if you are taking medicines to treat arrhythmia - fast, slow or irregular heart beat (e.g. quinidine, procainamide, amiodarone, sotalol).

Do not take this medicine if you are pregnant. Moxifloxacin is not recommended if you are pregnant.

Do not breastfeed if you are taking this medicine. Moxifloxacin passes into breast milk and may affect your baby.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • you or someone in your family has a history of heart rhythm problems
  • you are taking any medicine that might affect heart rhythm (e.g. quinidine, procainamide, amiodarone, sotalol, erythromycin, tricyclic antidepressants or antipsychotics)
  • you or someone in your family has a history of aneurysm disease or other vascular diseases
  • low potassium levels
  • any condition affecting the brain, particularly if you have ever had a seizure ('fit')
  • myasthenia gravis (a disease that causes muscle weakness)
  • severe liver problems
  • mental illness
  • diabetes

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Moxifloxacin may affect the electrocardiogram (ECG – an electrical record of the activity of the heart) and may add to the effect of other medicines on the ECG. You should advise your doctor if you are taking any medicine that might affect the heart rhythm.

Tell your doctor if you are taking:

  • warfarin, used to stop blood clots – your doctor should perform INR testing and may adjust your warfarin dose
  • medicines used to treat abnormal heart rhythm (e.g. quinidine, procainamide, amiodarone or sotalol)
  • medicines that can affect the heart rhythm (erythromycin, tricyclic antidepressants or antipsychotics)
  • corticosteroids

If you are taking any of these medicines, you may need a different dose, or you may need to take different medicines. Your doctor will advise you if you do.

The following medicines and moxifloxacin may affect each other or increase the chance of you getting a side effect. These include:

  • antacids, multivitamins, mineral supplements and other medicines containing iron, zinc, magnesium, aluminium or calcium
  • sucralfate, used to treat duodenal or stomach ulcers
  • didanosine, used to treat viral infections

You can still take these medicines while you are taking moxifloxacin.

However, you must take moxifloxacin at least 2 hours before, or 4 hours after taking any of these medicines to make sure there is no problem with absorption.

Other medicines not listed above may also interact with moxifloxacin.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The usual adult dosage for moxifloxacin tablets for most infections is one 400 mg tablet once daily for 5 to 10 days. However, some types of infections may require longer treatment. Your doctor will determine the duration of time that you take the tablets depending on the type of infection you have.

You should not exceed the dose your doctor has prescribed for you. The risk of heart rhythm problems may increase with an increase in dose.

How to take it

Swallow the tablet whole with water. Do not chew the tablet.

When to take it

Moxifloxacin tablets are usually taken once a day.

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take your medicine with or without food. It is advisable to drink plenty of fluids.

Do not take moxifloxacin at the same time as taking antacids (containing magnesium, calcium or aluminium), multivitamins (containing iron or zinc), sucralfate (a medicine to treat stomach ulcers) or didanosine (a medicine to treat viral infections). Taking these medicines at the same time as moxifloxacin can interfere with the absorption of moxifloxacin tablets and reduce their effectiveness in fighting the infection.

You must take moxifloxacin at least 2 hours before, or 4 hours after taking any of these medicines.

How long to take it for

The length of treatment with moxifloxacin tablets may vary depending on the type of infection. The usual duration of treatment is from five to ten days but can be longer. Your doctor will determine the duration of time that you need to take the tablets.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

If you develop an allergic reaction (e.g. skin rash) while taking this medicine, even following a single dose, stop taking it and tell your doctor.

Tell your doctor immediately if you get diarrhoea. Do this even if it occurs several weeks after you have stopped taking this medicine. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any medications for diarrhoea without checking with your doctor.

Tell your doctor immediately if you feel any discomfort, pain, swelling or inflammation of a tendon. Medicines like moxifloxacin have been reported to cause tendon damage (especially the Achilles tendon). This may occur even within the first 48 hours of treatment and up to several months after completing treatment with moxifloxacin. Elderly patients, patients taking a type of medicine called corticosteroids, patients with reduced kidney function or that have received solid organ transplants are more at risk.

Tell your doctor immediately if you experience palpitations (fast or irregular heart beat) or fainting spells during the period of treatment.

Tell your doctor if you experience symptoms of depression or self-endangering behaviour. This medicine should be discontinued.

Tell your doctor if you develop photosensitivity (getting sunburnt very easily). Avoid exposure to ultraviolet radiation and sunlight. Protect your skin when you are in the sun, especially between 10am and 3pm. If you are outdoors, wear protective clothing and use a 30+ sunscreen.

Tell your doctor if you develop pain, burning, tingling, numbness or weakness in any part of the body.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor first, especially if you are feeling better. If you do not complete the full course prescribed by your doctor, some of the bacteria causing your infection may not be killed. These bacteria may continue to grow and multiply so that your infection may not clear up completely or it may return.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. Moxifloxacin tablets may cause dizziness or faintness in some patients. The ability to drive and/or operate machinery may be impaired. If you drink alcohol, dizziness or faintness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking this medicine.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following and they worry you:

  • headache
  • dizziness or light headedness
  • nausea, vomiting
  • stomach pains, diarrhoea
  • thrush in the mouth (sore creamy yellow raised patches in mouth) or in the vagina (itching, burning or thick white discharge)

These are the more common side effects of this medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • palpitations or fainting spells
  • watery or bloody diarrhoea, even if it occurs several weeks after finishing your tablets
  • pain, swelling or rupture of a tendon
  • fits (seizures, convulsions)
  • visual disturbances or changes in vision (specialist consult needed)
  • pain, burning, tingling, numbness or weakness that starts or worsens on this medicine
  • changes in your mood or thoughts that worry you

The above list includes serious side effects and you may need medical attention.

In isolated instances, some serious side effects may be long-lasting (greater than 30 days) and disabling, such as tendonitis, tendon rupture, musculoskeletal disorders and other reactions affecting the nervous system including mental health disorders and disturbances of sense.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • hearing impairment
  • temporary visual impairment
  • sudden abdominal, chest or back pain
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

This medicine may cause rapid and severe inflammation of the liver, which can lead to life-threatening liver failure including fatal cases. Tell your doctor immediately if you suddenly feel unwell or sick and develop symptoms such as:

  • yellowing of the skin and in the whites of your eyes, also called jaundice
  • pain in liver area
  • dark urine
  • itchy skin
  • tendency to bleed

If you develop a skin reaction or blistering and/or peeling of the skin and/or mucosal reactions contact your doctor immediately before you continue the treatment.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some patients.

Some of these side-effects may also be long-lasting and disabling in some patients. If this occurs, speak to your doctor or pharmacist.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What Moxifloxacin APOTEX tablets looks like

400 mg film coated tablets: Reddish brown coloured, modified capsule-shaped, biconvex, film coated tablet engraved "APO" one side and "MX 400" on the other side. AUST R 223564.

Blister pack of 5 tablets.

Ingredients

Each tablet contains 400 mg moxifloxacin as the active ingredient.

It also contains the following inactive ingredients:

  • powdered cellulose
  • pregelatinised maize starch
  • croscarmellose sodium
  • silicon dioxide
  • magnesium stearate
  • polyvinyl alcohol
  • macrogol 8000
  • purified talc
  • titanium dioxide
  • iron oxide red

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia
Tel: (02) 8877 8333
Web: www1.apotex.com/au

APOTEX is registered trade mark of Apotex Inc.

This leaflet was last updated in December 2019.

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Moxifloxacin APOTEX

Active ingredient

Moxifloxacin

Schedule

S4

 

1 Name of Medicine

Moxifloxacin (as hydrochloride monohydrate).

6.7 Physicochemical Properties

Moxifloxacin is a synthetic broad spectrum antibacterial agent. It is a light yellow or yellow powder or crystal, which is slightly hygroscopic; it is sparingly soluble in water, slightly soluble in ethanol (96%) and practically insoluble in acetone. pKa values are 5.69 and 9.42.
Chemical Name: 1-cyclopropyl-7-{(S,S)-2,8-diaza-bicyclo[4.3.0]non-8-yl}- 6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid hydrochloride monohydrate.
Molecular Formula: C21H24FN3O4.HCl.H2O.
Molecular Weight: 455.91.

Chemical structure.


CAS number.

192927-63-2.

2 Qualitative and Quantitative Composition

Each film coated tablet contains 400 mg of moxifloxacin (as hydrochloride monohydrate) as the active ingredient.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

400 mg tablet.

Reddish brown coloured, modified capsule-shaped, biconvex film coated tablet engraved "APO" on one side and "MX 400" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Moxifloxacin is an 8-methoxyfluoroquinolone antibiotic with a broad spectrum of activity and bactericidal action. The bactericidal action results from the inhibition of topoisomerase II or DNA gyrase and topoisomerase IV required for bacterial DNA replication, transcription, repair and recombination.
Moxifloxacin exhibits concentration-dependent bactericidal killing. Minimum bactericidal concentrations are generally similar to minimum inhibitory concentrations. The mechanism of action for quinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. There is no known cross-resistance between moxifloxacin and other classes of antibiotics. Although cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria, Gram-positive bacteria resistant to other fluoroquinolones may be susceptible to moxifloxacin.
Moxifloxacin has been shown to be active against most strains of the following microorganisms (see Table 3), both in vitro and in clinical infections as described (see Section 4.1 Therapeutic Indications).
Moxifloxacin exhibits in vitro activity (MIC90 ≤ 2 microgram/mL) against the following microorganisms (see Table 4), but their clinical significance is unknown.
Moxifloxacin does not reliably show activity against Pseudomonas aeruginosa.

Resistance.

Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. Other resistance mechanisms such as permeation barriers and efflux mechanisms may, however, also affect the sensitivity of corresponding bacteria to moxifloxacin. Plasmid-mediated resistance has not been observed to date.
Cross resistance among quinolones has been observed. As moxifloxacin inhibits both topoisomerases II and IV, some Gram-positive bacteria and anaerobes that are resistant to other quinolones are susceptible to moxifloxacin.
The frequency of acquired resistance may vary geographically and with time for certain species. Local area information on resistance of organisms is desirable, particularly when treating severe infections.

Effect on the intestinal flora in humans.

In two volunteer studies, the following changes in intestinal flora were seen following dosing with moxifloxacin. E. coli, Bacillus spp., Bacteroides vulgatus, Enterococci and Klebsiella spp. were reduced, as were the anaerobes Bifidobacterium, Eubacterium and Peptostreptococcus. These changes returned to normal within two weeks. Clostridium difficile toxin was not found.

Susceptibility tests.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal and if the microorganism is not fully susceptible to alternative, clinically-feasible medicines, the test should be repeated. This category implies possible clinical applicability in body sites where the medicine is physiologically concentrated or in situations where high dosage of medicine can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Clinical trials.

In this section, overall clinical response is defined as the combined response rate at the end of treatment and follow-up visits (with failures at the end of treatment carried forward) in the per-protocol population. Bacteriological eradication is defined as eradication plus presumed eradication in microbiologically valid patients.

Acute bacterial exacerbation of chronic bronchitis.

Moxifloxacin tablets (400 mg once daily for 5 days) were evaluated for acute bacterial exacerbation of chronic bronchitis in two large randomised, double-blind, controlled clinical studies. Clarithromycin (500 mg twice daily) was used as the active control in both studies and the treatment duration was 7 days in one study (0124), and 10 days in the other (0127). The overall clinical response and bacteriological eradication rates for the most frequently isolated pathogens are shown in Table 5.

Community acquired pneumoniae.

Three large randomised, double-blind controlled clinical studies were conducted to evaluate the efficacy of moxifloxacin tablets (400 mg once daily for 10 days) in patients with clinically and radiologically documented community acquired pneumonia. Clarithromycin (500 mg twice daily for 10 days) was used as the active control in two studies (0119 and 0130) and high dose amoxycillin (1000 mg three times daily for 10 days) in the remaining one (0140). The results of these studies are shown in Table 6.

Sequential IV/oral therapy.

Two large, randomised, controlled trials were conducted to compare the efficacy of sequential IV/PO moxifloxacin 400 mg QD for 7-14 days in the treatment of patients with clinically and radiologically documented mild-moderate or severe community acquired pneumonia. A double-blind study enrolled 516 patients from the U.S. and Canada compared moxifloxacin to an IV/PO fluoroquinolone control. Another study enrolled 628 patients from Europe, Israel and South Africa, and compared moxifloxacin to sequential IV/PO amoxicillin/clavulanate (1.2 g IV q8h/625 mg PO q8h) with or without high-dose IV/PO clarithromycin (500 mg BID). The primary efficacy analysis was conducted in clinically evaluable patients at the test of cure visit (Day 7-30 post-therapy for NA Study and Day 5-7 post-therapy for Ex-NA Study). The clinical success rate for moxifloxacin therapy was equivalent to the fluoroquinolone comparators (86% vs. 89%). The clinical success for moxifloxacin therapy (93%) was higher than that for amoxicillin/clavulanate ± clarithromycin (85%) [95% C.I. for the treatment difference was 2.9-13.2%].
The microbiological eradication rates (eradication plus presumed eradication) in moxifloxacin-treated patients from these two trials were Streptococcus pneumoniae 93% (63/68), Streptococcus pneumoniae bacteremia 95% (19/20), Haemophilus influenzae 92% (23/25), Mycoplasma pneumoniae 96% (22/23) and Chlamydia pneumoniae 93% (13/14). Across all moxifloxacin tablet and intravenous community acquired pneumonia studies, the clinical success for Legionella pneumophila was 100% (6/6).

Acute bacterial sinusitis.

In a large randomised, double-blind controlled study, moxifloxacin tablets (400 mg once daily for 10 days) were compared with cefuroxime axetil (250 mg twice daily for 10 days) in the treatment of acute bacterial sinusitis. The results obtained from this study are shown in Table 7.

Skin and skin structure infections.

In a prospective, randomized, double-blind, active-control, multi-centre Phase III B clinical study (study number 100273), a total of 617 patients were randomised to one of the two treatment groups (sequential IV/p.o. moxifloxacin 400 mg qd versus piperacillin/tazobactam 3.0/0.375 g IV followed by p.o. amoxicillin/clavulanic acid suspension 800/114 mg bid). Subjects were enrolled with infections which included infected ischaemic or decubitus ulcers, diabetic foot infections, major abscesses, carbuncles, other SSTI requiring surgery, post-operative surgical infections and infected bite wounds. The clinical success rate (clinical cure or resolution) at the Test of Cure (TOC) visit was 79.4% (143/180) and 81.8% (153/187) for the moxifloxacin and comparator groups, respectively. Moxifloxacin was proven to be no less effective than the comparator regimen (95% CI: -12.04, +3.29).
In a second study prospective, non-blind, comparative, parallel group, multicentre, multinational Phase III clinical study (study number 10279) in patients with cSSSi with 804 patients, the patients were randomly and equally assigned to one of the two treatment groups: sequential IV/PO moxifloxacin 400 mg QD or amoxicillin/clavulanate 1000/200 mg IV followed by 500/125 mg PO TID, and maintained on a non-blind basis.
The clinical success rate at the TOC visit was 80.6% (254/315) and 84.5% (268/317) for the moxifloxacin and comparator groups, respectively. Moxifloxacin was proven to be no less effective than the comparator regimen (95% CI: -9.41, +2.18).
The clinical cure rates for the patients at TOC visit analysed by diagnosis type for each study are shown in Table 8.
The bacteriological eradication rates at TOC by baseline pathogen for selected organisms in the patients with causative organisms are shown in Table 9.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, moxifloxacin is absorbed rapidly and almost completely with an absolute bioavailability of approximately 90%.
Concomitant administration of moxifloxacin together with food slightly prolonged the time to reach peak concentrations by approximately 2 hours and slightly reduced peak concentrations by approximately 16%. Extent of absorption remained unchanged. As AUC/MIC is most predictive for antimicrobial efficacy of quinolones, this effect is clinically not relevant. Therefore, moxifloxacin can be administered independent from meals.
The mean (± SD) Cmax and AUC values following single and multiple doses of 400 mg moxifloxacin given orally or by 1 hour intravenous (IV) infusion are summarised in Table 10 and Figure 1.
Plasma concentrations increase proportionately with dose up to the highest dose tested (1200 mg single oral dose). The mean (± SD) elimination half-life from plasma is 12 ± 1.3 hours; steady-state is achieved after at least three days with a 400 mg once daily regimen.

Distribution.

The mean volume of distribution at steady state (Vss) is approximately 2 L/kg. In in vitro and ex vivo experiments, protein binding over a range of 0.02 to 2 mg/L resulted in a protein binding of approximately 40-42% independent of the drug concentration. Moxifloxacin is mainly bound to serum albumin.
Moxifloxacin is widely distributed throughout the body. Moxifloxacin has been detected in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses following oral or intravenous administration of 400 mg. Concentrations measured at 3 hours post-dose are summarised in Table 11. The rates of elimination of moxifloxacin from tissues generally parallel the elimination from plasma.
The peak concentrations and site vs. plasma concentration ratios for various target tissues yielded comparable results for both modes of drug administration after a single dose of 400 mg moxifloxacin.

Metabolism.

Moxifloxacin is metabolised via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism and is not affected by moxifloxacin. M1 and M2 are the only metabolites relevant in humans and both are microbiologically inactive. The sulfate conjugate (M1) accounts for approximately 38% of the dose and is eliminated primarily in the faeces. Approximately 14% of an oral or intravenous dose is converted to glucuronide conjugate (M2) which is excreted exclusively in the urine. Peak plasma concentrations of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less than 10% those of moxifloxacin.

Excretion.

Approximately 45% of an oral or intravenous dose is excreted as unchanged drug (~20% in urine and ~25% in faeces). A total of 96% ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean apparent total body clearance and renal clearance are approximately 12 L/h and 2.5 L/h, respectively, suggesting partial tubular reabsorption of the drug from the kidneys.

Special populations.

Geriatric.

In a study of 16 healthy, elderly male and female volunteers given a single oral 200 mg dose of moxifloxacin, the AUC, Cmax and elimination half-life were not statistically different between young and elderly subjects. In large Phase III studies, the pharmacokinetics in elderly patients following intravenous infusion of 400 mg were similar to those observed in young patients. Therefore, dosage adjustments based on age are not necessary.

Paediatric.

The pharmacokinetics of moxifloxacin have not been studied in paediatric patients.

Sex.

Following oral administration of 400 mg moxifloxacin daily for 10 days to 23 healthy males (19-75 years) and 24 healthy females (19-70 years), the mean AUC and Cmax were 8% and 16% higher, respectively, in females compared to males. Dosage adjustments based on sex are not necessary.

Interethnic differences.

Possible interethnic differences were examined in Caucasian, Japanese, Black and other ethnic groups. No clinically relevant interethnic differences in pharmacokinetics could be detected.

Renal impairment.

The pharmacokinetics of moxifloxacin are not significantly changed by renal impairment (including creatinine clearance < 30 mL/min/1.73 m2) and in patients on chronic dialysis i.e. haemodialysis and continuous ambulatory peritoneal dialysis. No dose adjustment is therefore required in patients with any degree of renal impairment (including creatinine clearance < 30 mL/min/1.73 m2). In a single oral dose study in patients with varying degrees of renal impairment not requiring dialysis, the mean AUC was increased by 13% in patients with moderate (Clcr ≥ 30 and ≤ 60 mL/min) and severe (Clcr < 30 mL/min) renal impairment. Mean AUC of the sulfate metabolite increased by 1.7-fold and the glucuronide increased by 2.8-fold.

Hepatic impairment.

Moxifloxacin plasma concentrations of patients with mild to severe hepatic impairment (Child-Pugh A to C) did not reveal clinically relevant differences compared to healthy volunteers or patients with normal hepatic function, respectively (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment for use in Child-Pugh C patients). In a single oral dose study in patients with stable chronic liver cirrhosis, concentrations of moxifloxacin were reduced by approximately 23% while concentrations of the sulfate metabolite were increased almost four-fold. No dosage adjustment for mild to moderate hepatic impairment is recommended. As limited clinical data are available in severe hepatic impairment (Child-Pugh C), the use of moxifloxacin in this patient group is not recommended.

Photosensitivity potential.

In a study of the skin response to ultraviolet and visible radiation conducted in 32 healthy volunteers (8 per group), no photosensitivity was produced by moxifloxacin. The minimum erythematous dose (MED) was measured before and after treatment with moxifloxacin (200 mg or 400 mg once daily), lomefloxacin (400 mg once daily) or placebo, and in this study, both doses of moxifloxacin were equivalent to placebo, while lomefloxacin significantly lowered the MED.

Drug-drug interactions.

The potential for pharmacokinetic drug interactions between moxifloxacin and theophylline, warfarin, digoxin, probenecid, ranitidine, glyburide, iron and antacids has been evaluated. No clinically significant drug-drug interactions were found with theophylline, warfarin, digoxin, probenecid, ranitidine or glibenclamide, but, as with all other quinolones, iron and antacids significantly reduced the bioavailability of orally administered moxifloxacin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There is limited information available on the potential for a pharmacodynamic interaction in humans between moxifloxacin and other medicines that prolong the QTc interval of the electro-cardiogram. In clinical trials, over 200 moxifloxacin-treated patients receiving drugs that prolong the QTc interval, 44 had electrocardiograms before and during moxifloxacin treatment. These patients demonstrated less of a change in QTc on moxifloxacin (1 ± 35 ms) than patients not receiving medicines that prolong the QTc interval (7 ± 25 ms). However, sotalol, a Class III antiarrhythmic, has been shown to further increase the QTc interval when combined with intravenous (IV) moxifloxacin in dogs. Therefore, moxifloxacin should not be used with Class IA or Class III antiarrhythmics (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Moxifloxacin was not mutagenic in 4 of 5 strains in the Salmonella reversion assay, however, as with other quinolones, a positive response was observed in strain TA 102. This may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay and gave an equivocal result in the V79/HGPRT mammalian cell gene mutation assay. Moxifloxacin was clastogenic in the v79 chromosome aberration assay in vitro but inactive in vivo in dominant lethal and micronucleus tests in mice. Moxifloxacin was inactive in an assay for unscheduled DNA synthesis in vitro.

Carcinogenicity.

Conventional long-term carcinogenicity studies in rodents have not been carried out. Moxifloxacin at an oral dose of 459 mg/kg/day, was inactive in a limited 38-week tumour-initiation-promotion bioassay in rats. This dose resulted in a systemic drug exposure that was 1.9 times (males) and 0.3 (females), compared with the clinical exposure at the maximum recommended clinical exposure (AUC).

4 Clinical Particulars

4.1 Therapeutic Indications

Moxifloxacin tablets are indicated for the treatment of adults with infections caused by susceptible organisms in the conditions:
Acute bacterial sinusitis;
Community acquired pneumonia;
Acute exacerbations of chronic bronchitis.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to moxifloxacin. Therapy with moxifloxacin may be initiated, in some conditions, before results of these tests are known. Once results become available, therapy should be continued with the most appropriate antibiotic therapy.
Consideration should be given to available official guidance on the appropriate use of antibacterial agents.

4.3 Contraindications

Known hypersensitivity to moxifloxacin or to any other quinolones or any of the excipients in this medicine.
Because of an effect of moxifloxacin on the QTc interval of the electrocardiogram and a lack of clinical experience with the medicine in the following patient populations, the drug is contraindicated in patients with known prolongation of the QTc interval, patients with uncorrected hypokalaemia and patients receiving Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic agents (see Section 4.4 Special Warnings and Precautions for Use).
See Section 4.4 Special Warnings and Precautions for Use, General, Paediatric use; Section 4.2 Dose and Method of Administration, Paediatric.

4.4 Special Warnings and Precautions for Use

Fluoroquinolones, including moxifloxacin, have been associated with disabling and potentially persistent adverse reactions involving different body systems that have occurred together in the same patient. These include, but are not limited to, serious adverse reactions involving the nervous system (see Psychiatric reactions below) and musculoskeletal system (see Tendonitis and tendon rupture below).

General.

The safety and effectiveness of moxifloxacin in paediatric patients, adolescents (less than 18 years of age), pregnant women and lactating women have not been established (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy, Use in lactation; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Cardiac effects.

At high concentrations, moxifloxacin is an inhibitor of the delayed rectifier potassium current of the heart. Moxifloxacin has been shown to prolong the QTc interval in some patients. The magnitude of this effect may increase with increasing concentrations of the drug, therefore the recommended dose or infusion rate (400 mg within 60 minutes) should not be exceeded. QTc prolongation may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) and cardiac arrest.
In 787 patients receiving oral treatment with paired valid ECGs in Phase III clinical trials, the mean ± SD effect of moxifloxacin 400 mg on the QTc interval was small (6 ± 26 ms). 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.
Following a course of daily intravenous dosing (400 mg; 1 hour infusion each day) the mean change in QTc from the Day 1 pre-dose value was 9 ms (± 24) on Day 1 (n = 69) and 3 ms (± 29) on Day 3 (n = 290). In sequential IV/oral trials in community acquired pneumonia, QT interval prolongation was reported in 1.3% (6/550) in the moxifloxacin group and 0.7% (4/579) in the comparator group. No cases of ventricular arrhythmia associated with QT interval prolongation were observed in these studies.
No cardiovascular morbidity or mortality was attributed to moxifloxacin among over 5000 patients treated with oral moxifloxacin including 223 patients who were hypokalaemic at the start of treatment.
Due to limited clinical experience, patients with uncorrected electrolyte disorders particularly hypokalaemia, known prolongation of the QTc interval or those concurrently receiving drugs that prolong the QTc interval, in particular Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmics, should not receive moxifloxacin. An additive effect of moxifloxacin and medicines that prolong the QT interval such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants cannot be excluded, therefore moxifloxacin should be used with caution when given concurrently with these medicines. The effect of moxifloxacin on patients with congenital prolongation of the QTc interval has not been studied, however, it is expected that these individuals may be more susceptible to drug-induced QTc prolongation.
Moxifloxacin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients), such as clinically significant bradycardia and acute myocardial ischaemia.

Antibiotic-associated colitis.

Pseudomembranous colitis has been reported with virtually all broad spectrum antibiotics including moxifloxacin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life-threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with moxifloxacin use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, appropriate therapy, such as oral antibacterial agents effective against Clostridium difficile, should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs inhibiting peristalsis are contraindicated in patients who develop serious diarrhoea.

Tendonitis and tendon rupture.

Tendonitis and tendon rupture (predominantly Achilles tendon), sometimes bilateral, that required surgical repair or resulted in prolonged disability have been reported with quinolone therapy including moxifloxacin. This may occur even within the first 48 hours of treatment, and cases occurring up to several months after completion of therapy have been reported. The risk of tendinopathy may be increased in elderly patients, during strenuous physical activity, in patients treated concomitantly with corticosteroids, in patients with renal impairment and in patients with solid organ transplants. At the first sign of tendonitis (e.g. painful swelling, inflammation) the affected extremity should be kept at rest, any inappropriate physical exercise should be avoided, a physician should be consulted and moxifloxacin should be discontinued.

Seizures.

Seizures may occur with quinolone therapy. Moxifloxacin should be used with caution in patients with known or suspected CNS disorders (e.g. lowered convulsion threshold, previous history of convulsion, reduced cerebral blood flow, altered brain structure or stroke) that may predispose them to seizures or lower the seizure threshold.

Myasthenia gravis.

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

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias or weakness have been reported in patients receiving quinolones including moxifloxacin. Moxifloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness and/or weakness in order to prevent the development of an irreversible condition (see Section 4.8 Adverse Effects (Undesirable Effects)).

Psychiatric reactions.

Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of psychiatric adverse reactions including toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations or paranoia, depression or self-injurious behaviour such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving moxifloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the medicine and institute appropriate care.

Use in hepatic impairment.

As limited clinical data are available in severe hepatic impairment (Child-Pugh C), the use of moxifloxacin in this patient group is not recommended. Cases of fulminant hepatitis potentially leading to life-threatening liver failure (including fatal cases) have been reported with moxifloxacin (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing adverse event reports). Patients should be advised to contact their doctor prior to continuing treatment if signs and symptoms of 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.

Vision disorders.

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see Section 4.8 Adverse Effects (Undesirable Effects)).

Photosensitivity potential.

Phototoxicity has been reported with other quinolones. However, in specially designed preclinical and clinical studies photosensitivity has not been observed with moxifloxacin. In addition, since first marketed there has been no clinical evidence that moxifloxacin causes photosensitivity reactions. Nevertheless patients should be advised to avoid extensive exposure to either UV irradiation or sunlight.

Hypersensitivity reactions.

Hypersensitivity and allergic reactions have been reported following the first dose. In very rare instances these can progress to life-threatening shock. Moxifloxacin should be discontinued and appropriate therapy commenced in these cases.
Anaphylactic reactions in very rare instances can progress to a life-threatening shock, in some instances after the first administration. In these cases, the treatment with moxifloxacin has to be discontinued, medical treatment (e.g. treatment for shock) is required.

Skin reactions.

Cases of bullous skin reaction like Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported with moxifloxacin (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing adverse event reports). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Osteomyelitis.

In patients with complicated skin and skin structure infection who have associated osteomyelitis there are no data demonstrating the efficacy and safety of treatment with moxifloxacin.

Dysglycaemia.

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia, have been reported with moxifloxacin. In moxifloxacin-treated patients, dysglycaemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. sulfonylurea) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)).

Aortic aneurysm and dissection.

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.

Other.

Moxifloxacin is not recommended for the treatment of methicillin resistant Staphylococcus aureus (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 Pharmacodynamic Properties, Mechanism of action).
Moxifloxacin in vitro activity may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth, causing false negative results in specimens from patients currently taking moxifloxacin.

Use in the elderly.

No data available.

Paediatric use.

The oral administration of moxifloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight bearing joints and other signs of arthropathy in immature animals of various species. Therefore, moxifloxacin should not be used in paediatric patients.

Effects on laboratory tests.

No data available.

Information for patients.

To assure safe and effective use of moxifloxacin, the following information and instruction should be communicated to the patient when appropriate.
Patients should be advised of the following.
That moxifloxacin may produce an effect on the electrocardiogram and may add to the effect of other medicines on the electrocardiogram. Consequently, patients should advise their physician of any other medications that they are currently taking, including over-the-counter medications.
That the recommended dose should not be exceeded.
To inform their physician of any personal or family history of QT prolongation.
To contact their physician if they experience palpitations or fainting spells while taking moxifloxacin.
That moxifloxacin tablets may be taken with or without meals, and to drink fluids liberally.
That moxifloxacin tablets should be taken at least 2 hours before or 4 hours after multivitamins (containing iron or zinc), antacids (containing magnesium, calcium or aluminium), sucralfate or didanosine chewable/buffered tablets or the paediatric powder for oral solution (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
That moxifloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the medicine at the first sign of a skin rash or other signs of an allergic reaction.
To discontinue treatment, rest and refrain from exercise, and inform their physician if they experience pain, inflammation or rupture of a tendon.
That moxifloxacin may cause dizziness and light-headedness; therefore, patients should know how they react to this medicine before they operate an automobile or machinery or engage in activities requiring mental alertness or co-ordination.
That convulsions have been reported in patients receiving quinolones and they should notify their physician before taking this drug if there is any history of this condition.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs which can affect moxifloxacin.

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use for medicines known to prolong the QT interval.

Antacids, minerals and multi-vitamins.

Concomitant ingestion of moxifloxacin together with antacids, minerals and multi-vitamins may result in impaired absorption of moxifloxacin due to the formation of chelate complexes with the multivalent cations contained in these preparations. This may lead to lower than desired plasma concentrations. Hence, oral doses of moxifloxacin should be administered at least 2 hours before or 4 hours after ingestion of antacids and other preparations containing magnesium, aluminium, sucralfate and other minerals, such as iron or zinc.

Anti-retroviral medicines.

Oral doses of moxifloxacin should be administered at least 2 hours before or after ingestion of antacid buffered anti-retroviral drugs (e.g. didanosine).

Drugs shown not to affect moxifloxacin.

For the following substances, absence of a clinically relevant interaction with moxifloxacin was proven: atenolol, ranitidine, calcium supplements, theophylline, oral contraceptives, glibenclamide, itraconazole, digoxin, morphine and probenecid. No dose adjustment is necessary for these drugs.

Ranitidine.

The concomitant administration with ranitidine did not change the absorption characteristics of moxifloxacin significantly. Absorption parameters (Cmax, tmax, AUC) were very similar, indicating an absence of influence of gastric pH on moxifloxacin uptake from the gastrointestinal tract.

Calcium supplements.

When given with high-dose calcium supplements, only a slightly reduced rate of absorption was observed, while extent of absorption remained unaffected. The effect of high-dose calcium supplements on the absorption of moxifloxacin is considered as clinically not relevant.

Warfarin.

No interaction during concomitant treatment with warfarin on prothrombin time and other coagulation parameters has been observed.
Changes in INR (International Normalized Ratio): Cases of increased anticoagulant activity have been reported in patients receiving oral anticoagulants concurrently with antibiotics, including moxifloxacin. The infectious disease (and its accompanying inflammatory process), age and general status of the patient are risk factors. Although an interaction between moxifloxacin and warfarin was not demonstrated in clinical trials, INR monitoring should be performed and, if necessary, the oral anticoagulant dosage should be adjusted as appropriate.

Oral contraceptives.

No interaction has occurred following concomitant oral administration of moxifloxacin with oral contraceptives.

Itraconazole.

Exposure (AUC) to itraconazole was only marginally altered under concomitant moxifloxacin treatment. Pharmacokinetics of moxifloxacin were not significantly altered by itraconazole. No dose adjustment is necessary for itraconazole when given with moxifloxacin and vice versa.

Digoxin.

The pharmacokinetics of digoxin are not significantly influenced by moxifloxacin (and vice versa). After repeated dosing in healthy volunteers moxifloxacin increased Cmax of digoxin by approximately 30% at steady state without affecting AUC or trough levels.

Morphine.

Parenteral administration of morphine with moxifloxacin did not reduce the oral bioavailability of moxifloxacin and only slightly decreased Cmax (17%).

Atenolol.

The pharmacokinetics of atenolol are not significantly altered by moxifloxacin. Following single dose administration in healthy subjects, AUC was marginally increased (by approximately 4%) and peak concentrations were decreased by 10%.

Theophylline.

No influence of moxifloxacin on theophylline pharmacokinetics (and vice versa) at steady state was detected, indicating that moxifloxacin does not interfere with the 1A2 subtypes of the cytochrome P450 enzymes; theophylline concentrations were not elevated at steady state during combined treatment with moxifloxacin (Cmax 10.5 vs 10.1 mg/L, without vs with theophylline).

Probenecid.

No significant effect on apparent total body clearance and renal clearance of moxifloxacin was found in a clinical study investigating the impact of probenecid on renal excretion. Therefore, dosing adjustments need not be made when both drugs are administered concurrently.

Antidiabetic agents.

No clinically relevant interaction was seen between glibenclamide and moxifloxacin.

Use of countermeasures.

Concomitant dosing of charcoal and 400 mg oral moxifloxacin reduced the systemic availability of moxifloxacin by more than 80% by preventing absorption in vivo. The application of activated charcoal in the early absorption phase prevents further increase of systemic exposure in cases of overdose.
After intravenous drug administration, carbo medicinalis only slightly reduces systemic exposure (approx. 20%).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Oral treatment of male rats with a dose of 500 mg/kg/day moxifloxacin (about 2.5 times clinical exposure, based on AUC) or an intravenous dose of 45 mg/kg/day (about 0.5 times clinical exposure, based on the estimated AUC) had no effect on fertility. At the oral dose of 500 mg/kg/day there were slight effects on sperm morphology (head-tail separations) in male rats.
Female rat fertility was unaffected by the same oral moxifloxacin dose, which resulted in a low relative systemic drug exposure (0.4 times clinical exposure) and slightly reduced oestrus cycling. Female rat fertility was also unaffected by an IV dose of 45 mg/kg/day (about 0.3 times clinical exposure, based on the estimated AUC).
(Category B3)
Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs.
Moxifloxacin was not teratogenic in Cynomolgus monkeys administered oral doses of 100 mg/kg/day moxifloxacin (approximately 2 times clinical exposure at the maximum recommended dose based on AUC). Doses of 30 mg/kg/day and above (about 0.6 times clinical exposure in terms of the AUC) resulted in embryonic deaths and abortions. An increased incidence of smaller foetuses was observed at doses of 100 mg/kg/day.
Teratogenicity was not seen in a study in rats, but the highest oral dose used (500 mg/kg/day) resulted in a lower (0.25 times) plasma drug exposure than would have been expected during therapy. The same oral dose given to rats from early gestation through to weaning was maternotoxic and was associated with reduced pup weights and increased perinatal mortality. Intravenous administration of 80 mg/kg/day to pregnant rats resulted in maternal toxicity and a marginal effect on fetal and placental weights and the appearance of the placenta. There was no evidence of teratogenicity at intravenous doses as high as 80 mg/kg/day (at least 0.2 x clinical exposure, based on AUC).
Intravenous administration of 20 mg/kg/day moxifloxacin (approximately equal to clinical exposure in terms of the AUC) to rabbits resulted in decreased fetal body weights, delayed fetal skeletal ossification, an increased incidence of fetuses and litters with malformations and an increased incidence of fetuses with prominent liver lobulation. Maternal toxicity in rabbits at 20 mg/kg/day intravenously included mortality, abortions, reduction of food consumption, decreased water intake, body weight loss and hypoactivity.
There are no adequate or well-controlled studies in pregnant women and because of the above findings in animal teratology studies, moxifloxacin therapy during pregnancy is not recommended.
 Preclinical evidence indicates that small amounts of moxifloxacin may be secreted in human milk. Because of the potential for serious adverse reactions in infants nursing from mothers taking moxifloxacin, a decision should be made whether to discontinue nursing or to discontinue moxifloxacin, taking into account the importance of the drug to the mother.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions (ADRs) based on all clinical studies with moxifloxacin 400 mg (oral and sequential therapy), sorted by CIOMS III categories of frequency (overall n = 12,984, including n = 2,535 for sequential therapy studies; status: December 2005), are listed on Table 2.
ADRs listed under "common" were observed with a frequency below 3% with the exception of nausea and diarrhoea.
Within each frequency grouping, the ADRs are presented in order of decreasing seriousness. Frequencies are defined as: Common ≥ 1/100 to < 1/10; Uncommon ≥ 1/1000 to < 1/100; Rare ≥ 1/10,000 to < 1/1000; Very rare < 1/10,000.
In isolated instances, some serious adverse drug reactions may be long-lasting (> 30 days) and disabling; such as tendonitis, tendon rupture, musculoskeletal disorders, and other reactions affecting the nervous system including psychiatric disorders and disturbance of senses.
The following undesirable effects have a higher frequency in the subgroup of IV/oral sequentially treated patients:
Common: Increased gamma-glutamyl-transferase.
Uncommon: Hallucination, seizures of various clinical manifestations (incl. grand mal convulsions), hypotension, oedema, antibiotic-associated colitis (in very rare cases associated with life-threatening complications), ventricular tachyarrhythmias, renal impairment and renal failure (due to dehydration esp. in elderly with pre-existing renal disorders).

Post-marketing adverse event reports.

Cardiovascular system disorders.

Very rare (< 0.01%): cardiac arrest and torsade de pointes, and usually in patients with concurrent severe underlying proarrhythmic conditions such as clinically significant bradycardia, acute myocardial ischaemia.

Hepatobiliary disorders.

Very rare (< 0.01%): fulminant hepatitis potentially leading to life-threatening liver failure (including fatal cases).

Musculoskeletal, connective tissue and bone disorders.

Very rare (< 0.01%): tendon rupture, gait disturbance (caused by muscular, tendon or joint symptoms), exacerbation of symptoms of myasthenia gravis.

Psychiatric disorders.

Very rare (< 0.01%): depression and/or psychotic reactions potentially culminating in self-injurious behaviour such as suicidal ideational thoughts or suicide attempts.

Nervous system disorders.

Very rare (< 0.01%): disturbed coordination leading to fall with injuries (esp. in elderly).

Skin and subcutaneous tissue disorders.

Very rare (< 0.01%): bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening).

Renal and urinary disorders.

Uncommon (≥ 0.1% to < 1%): dehydration (caused by diarrhoea or reduced fluid intake).

Metabolism and nutrition disorders.

Hypoglycaemia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Moxifloxacin APOTEX film coated tablets are intended for oral administration.

Dosage.

The usual dose of moxifloxacin is 400 mg orally or intravenously every 24 hours. The recommended dose should not be exceeded.

Note.

A moxifloxacin intravenous solution is not available in this brand.
The duration of therapy depends on the type of infection as described in Table 1.
The recommended duration of therapy for the treatment indication should not be exceeded.
Oral doses should be administered at least two hours before or four hours after antacids containing magnesium or aluminium, products containing iron or multivitamins containing zinc. The film-coated tablet should be swallowed whole with sufficient liquid and may be taken independent of meals.
When switching from intravenous to oral dosage administration, no dosage adjustment is necessary. Patients whose therapy is started with moxifloxacin IV may be switched to moxifloxacin tablets when clinically indicated at the discretion of the physician.

Dose adjustments.

Elderly.

No adjustment of dose is necessary.

Paediatric.

The use of moxifloxacin in children is not recommended (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Interethnic differences.

No adjustment of dosage is required in different ethnic groups.

Hepatic impairment.

No dosage adjustment is required in patients with impaired liver function. As limited clinical data are available in severe hepatic impairment (Child-Pugh C), the use of moxifloxacin in this patient group is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment for use in Child-Pugh C patients).

Renal impairment.

No dosage adjustment is required in renally-impaired patients (including patients whose creatinine clearance ≤ 30 mL/min/1.73 m2) and in patients on chronic dialysis i.e. haemodialysis and continuous ambulatory peritoneal dialysis.

Directions to administer.

The extent of absorption (AUC) of moxifloxacin was not altered when administered with food. Therefore, moxifloxacin can be taken independently from food intake.

4.7 Effects on Ability to Drive and Use Machines

Moxifloxacin may cause dizziness and light-headedness; therefore, patients should know how they react to this medicine before they operate an automobile or machinery, or engage in activities requiring mental alertness or co-ordination.
Fluoroquinolones including moxifloxacin may result in an impairment of the patient's ability to drive or operate machinery due to CNS reactions and vision disorders (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.9 Overdose

Only limited data on overdose are available. Single oral doses of up to 2.8 g and multiple doses of 600 mg over 10 days were administered to healthy subjects without any significant undesirable effects.

Treatment.

In the event of overdosage it is recommended that appropriate supportive care should be instituted as dictated by the patient's clinical status. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase in systemic moxifloxacin exposure. Due to the potential for moxifloxacin to cause QT prolongation, patients should be carefully monitored following an overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powdered cellulose, pregelatinised maize starch, croscarmellose sodium, silicon dioxide, magnesium stearate, polyvinyl alcohol, macrogol 8000, purified talc, titanium dioxide, iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

400 mg tablet: Blister pack (Al/Al or PVC/PVdC/Al) of 5 tablets (AUST R 223564).
APOTEX is a registered trade mark of Apotex Inc.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes