Consumer medicine information

Avelox IV

Moxifloxacin

BRAND INFORMATION

Brand name

Avelox

Active ingredient

Moxifloxacin

Schedule

SUMMARY CMI

AVELOX^® IV

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using AVELOX IV?

AVELOX IV contains the active ingredient moxifloxacin. AVELOX IV is used in adults for the treatment of serious infections of the lungs and airways. It can also be used to treat severe, complicated skin and skin structure infections.

For more information, see Section 1. Why am I using AVELOX IV? in the full CMI.

2. What should I know before I am given AVELOX IV?

Do not use if you have ever had an allergic reaction to AVELOX IV or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, in particular heart rhythm problems, severe liver problems, seizures, mental illnesses or if you have a sodium restriction, if you are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given AVELOX IV? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with AVELOX IV and affect how it works.

The main types of medicines that affect how AVELOX works include warfarin, medicines to treat abnormal heart rhythm, medicines which affect heart rhythm and corticosteroids.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given AVELOX IV?

Avelox IV is normally given as a slow injection into a vein over a period of 60 minutes (‘drip’) once daily for 5-21 days. Avelox IV must only be given by a doctor or a nurse at the hospital.

More information can be found in Section 4. How am I given AVELOX IV? in the full CMI.

5. What should I know while using AVELOX IV?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using AVELOX IV. Avoid exposure to ultraviolet radiation and sunlight. Call your doctor immediately if you experience allergic reaction, diarrhoea, feel any discomfort, pain, swelling or inflammation of a tendon, palpitations, symptoms of depression or self-harming, develop pain, burning, tingling, numbness or weakness in any part of the body, or develop photosensitivity.
Things you should not do	Do not interfere with the equipment that is used to infuse AVELOX IV into your body
Driving or using machines	AVELOX IV may cause dizziness or faintness in some people. Be careful before you drive or use any machines until you know how AVELOX affects you.

For more information, see Section 5. What should I know while receiving AVELOX IV? in the full CMI.

6. Are there any side effects?

Less serious side effects may include redness or pain at the site of injection, headache, dizziness, nausea, vomiting, stomach pains, thrush in the mouth or vagina.

Serious side effects may include allergic reactions, palpitations, fainting, seizures, diarrhoea, tendon pain, swelling or rupture, pain, burning, tingling, numbness or weakness that starts or worsens on AVELOX IV, eyesight problems, changes in mood or thoughts, skin reactions, blistering or peeling, and symptoms of liver damage.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

BOXED WARNING:

Serious disabling and potentially irreversible adverse reactions

Fluoroquinolones, including moxifloxacin, have been associated with disabling and potentially irreversible serious adverse reactions involving different body systems that have occurred together in the same patient. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. These include but are not limited to serious adverse reactions involving the nervous system (Seizures, Peripheral neuropathy), musculoskeletal system (Tendonitis and tendon rupture) and psychiatric effects (Psychiatric reactions).

FULL CMI

AVELOX^® IV (AV·e·lox)

Active ingredient(s): moxifloxacin hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using AVELOX IV. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using AVELOX IV.

Where to find information in this leaflet:

1. Why am I using AVELOX IV?
2. What should I know before I am given AVELOX IV?
3. What if I am taking other medicines?
4. How am I given AVELOX IV?
5. What should I know while receiving AVELOX IV?
6. Are there any side effects?
7. Product details

1. Why am I using AVELOX IV?

AVELOX IV contains the active ingredient moxifloxacin.
AVELOX IV is a sterile intravenous antibiotic belonging to a group of medicines called quinolones. These antibiotics work by killing the bacteria that are causing your infection.

AVELOX IV is used in adults for the treatment of serious infections of the lungs and airways. It can also be used to treat severe, complicated skin and skin structure infections.

Avelox IV is used to start the treatment and then your doctor may prescribe tablets to complete the course.

Remember to read the Consumer Medicine Information for Avelox tablets, if you receive them, because it may contain additional information specific to the tablets.

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

2. What should I know before I am given AVELOX IV?

Warnings

Do not use AVELOX IV if:

you are allergic to moxifloxacin, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine
you are allergic to other medicines belonging to the quinolone family (e.g. ciprofloxacin, norfloxacin, nalidixic acid)
you have a condition called ‘QTc prolongation’ which is a type of abnormal heart rhythm
you are taking medicines to treat arrhythmia – fast, slow or irregular heartbeat (e.g. quinidine, procainamide, amiodarone, sotalol)
you have a blood test that shows lower than normal potassium levels

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition
you or someone in your family has a history of heart rhythm problems
are taking any medicine that might affect heart rhythm (e.g. quinidine, procainamide, amiodarone, sotalol, erythromycin, tricyclic antidepressants, antipsychotics)
have low potassium levels
have had any condition affecting the brain, particularly if you have ever had a seizure (‘fit’)
have severe liver problems
have a condition called myasthenia gravis (a disease causing muscle weakness)
have or had a mental illness
have diabetes

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

AVELOX IV is not recommended if you are pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

AVELOX IV passes into breast milk and may affect your baby.

Children under 18 years old

AVELOX should not be used in children under 18 years of age.

Restricted Sodium Intake

Some medical conditions may require a restricted sodium intake (e.g. congestive heart failure, kidney failure, kidney disease). Tell your doctor if you have a condition like this because AVELOX IV solution contains sodium salt. The additional sodium you receive may worsen the symptoms of these conditions.

3. What if I am taking other medicines?

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

Some medicines may interfere with AVELOX IV and affect how it works.

AVELOX may have an effect on the heart rhythm. If you are using other medicines that affect the heart at the same time as AVELOX there is an increased risk of altering your heart rhythm.

Tell your doctor if you are taking:

warfarin, a medicine 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, sotalol)
medicines that can affect the heart rhythm (e.g. erythromycin, tricyclic antidepressants, antipsychotics)
corticosteroids

These medicines and Avelox may affect each other or increase the chance of you getting a side effect.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect AVELOX IV.

4. How am I given AVELOX IV?

Avelox IV must only be given by a doctor or a nurse at the hospital.
Avelox IV is given as a slow injection into a vein over a period of 60 minutes (‘drip’).

How much is given?

The usual adult dose is 400mg once a day for 5-21 days.
Your doctor will determine the dose and duration of time that you are given Avelox IV depending on your infection. Your doctor will put you on Avelox tablets as soon as possible, after being given Avelox IV.

If you are given too much AVELOX IV

If you think that you have received too much AVELOX IV, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while receiving AVELOX IV?

Things you should do

Avoid prolonged exposure to ultraviolet radiation and sunlight. AVELOX can make your skin more susceptible to sunburn. Protect your skin when you are in the sun, especially between 10am and 3pm. If you are outdoors, wear protective clothing and use a SPF 30+ sunscreen.

Call your doctor straight away if you:

develop an allergic reaction (e.g. skin rash) while on Avelox IV, even following a single dose.
develop diarrhoea. Contact your doctor even if it occurs several weeks after you have finished receiving AVELOX IV.
feel any discomfort, pain, swelling or inflammation of a tendon.
experience palpitations (fast or irregular heart beats) or fainting spells during treatment.
experience symptoms of depression or self-harming behaviour. AVELOX should be discontinued.
develop pain, burning, tingling, numbness or weakness in any part of the body. AVELOX should be discontinued immediately.
develop photosensitivity (getting sunburnt very easily)

Remind any doctor, dentist or pharmacist you visit that you are using AVELOX IV.

Things you should not do

Do not interfere with the equipment that is used to infuse AVELOX IV into your body. Changes to the settings of the equipment must only be carried out by your doctor or the nurse who is looking after you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how AVELOX IV affects you.

AVELOX IV may cause dizziness or faintness in some people. Be careful before you drive or use any machines or tools until you know how AVELOX IV affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

How is AVELOX IV stored?

AVELOX IV will be stored in the pharmacy or on the ward.
It is kept in a cool, dry place away from sunlight, where the temperature stays below 30°C and above 15°C. Do not refrigerate.

Getting rid of any unwanted medicine

Each pack of AVELOX IV is to be used once only. Any unused portion must be returned to the pharmacist for disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Tell your doctor or nurse as soon as possible if you do not feel well while you are receiving Avelox IV.

Less serious side effects

Less serious side effects

What to do

Nervous system-related:

headache
dizziness or light-headedness

Gastrointestinal system-related:

nausea, vomiting
stomach pains, diarrhoea

Fungal infection

thrush in the mouth (sore creamy-yellow raised patches in mouth) or in the vagina (itching, burning or thick white discharge)

Skin-related

redness or pain at the site of injection

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Immune-related:

allergic reactions such as skin rashes, swelling of the face, lips, mouth or throat

Nervous system-related:

palpitations or fainting spells
fits (seizures, convulsions)

Gastrointestinal system-related:

watery or bloody diarrhoea, even if it occurs several weeks after finishing your AVELOX treatment.
It may be a sign 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.

Muscle-related:

pain, swelling or rupture of a tendon
pain, burning, tingling, numbness or weakness that starts or worsens on AVELOX

Eye-related:

visual disturbances (eyesight problems)

Mood-related:

changes in your mood or thoughts that worry you

Liver damage:
suddenly feeling 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

Skin-related:

skin reaction or blistering and/or peeling of the skin and/or mucosal reactions

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What AVELOX IV contains

Active ingredient (main ingredient)	moxifloxacin (as hydrochloride) 400 mg per 250 mL
Other ingredients (inactive ingredients)	sodium chloride water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What AVELOX IV looks like

AVELOX IV is a ready to use, clear yellow solution for infusion.

Avelox IV is available in flexibags in packs of 1, 5 and 12 (Aust R 78977).

It is also made in glass bottles in packs of 1 and 5 (Aust R 81598).

Not all forms and pack sizes may be marketed.

Who distributes AVELOX IV

Bayer Australia Ltd.
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

® Registered Trademark of Bayer Group, Germany

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

This leaflet was revised in September 2024.

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Avelox

Active ingredient

Moxifloxacin

Schedule

1 Name of Medicine

Moxifloxacin hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 436.8 mg moxifloxacin hydrochloride, equivalent to 400 mg moxifloxacin.
Each 250 mL solution for infusion contains 436.8 mg moxifloxacin hydrochloride, equivalent to 400 mg moxifloxacin in 0.8% sodium chloride. The solution for infusion (250 mL) contains 34 mmol sodium.

3 Pharmaceutical Form

Avelox 400 mg tablets are dull red, oblong, convex film-coated tablets with BAYER on one side and M 400 on the other.
Avelox 400 mg tablets contains lactose monohydrate.
Avelox IV is a sterile, preservative free aqueous solution of moxifloxacin hydrochloride with pH ranging from 4.1 to 4.6. The appearance of the intravenous solution is yellow. The colour does not affect, nor is it indicative of, product stability.
For the full list of excipients, see Section 6.1 List of Excipients.

4 Clinical Particulars

4.1 Therapeutic Indications

Avelox (moxifloxacin hydrochloride) tablets are indicated for the treatment of adults with infections caused by susceptible organisms in the following conditions:
acute bacterial sinusitis;
community acquired pneumonia;
acute exacerbations of chronic bronchitis.
Avelox IV (moxifloxacin hydrochloride) intravenous solutions are indicated for treatment of adults who require initial IV therapy for the treatment of infections in the following conditions:
community acquired pneumonia (caused by susceptible organisms);
acute exacerbations of chronic bronchitis when caused by organisms bacteriologically proven to be resistant to other classes of antibiotics or when there is intolerance to other antibiotics.
Avelox IV (moxifloxacin hydrochloride) intravenous solutions are indicated for treatment of adults with severe and complicated skin and skin structure infections who require initial parenteral therapy, and who have intolerance to alternative agents, (especially penicillin allergy), and when caused by organisms known to be susceptible to moxifloxacin.
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 Avelox 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.

4.2 Dose and Method of Administration

Dose.

The usual dose of Avelox is 400 mg orally or intravenously every 24 hours. The recommended dose should not be exceeded. Avelox IV is recommended for the treatment of adults in its approved indications who require initial IV therapy (see Section 4.1 Therapeutic Indications). 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 Avelox IV may be switched to Avelox tablets when clinically indicated at the discretion of the physician.

Method of administration.

Avelox IV (moxifloxacin) should be administered by intravenous infusion only. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal or subcutaneous administration.
Avelox IV should be administered by intravenous infusion over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in place. Caution: rapid or bolus intravenous infusion must be avoided.
Since only limited data are available on the compatibility of moxifloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to Avelox IV or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of other drugs, the line should be flushed before and after infusion of Avelox IV with an infusion solution compatible with Avelox IV as well as with other drug(s) administered via this common line.
In patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephrotic syndrome, etc.) the additional sodium load of the solution for infusion should be taken into account.
The extent of absorption (AUC) of moxifloxacin was not altered when administered with food. Therefore, Avelox can be taken independently from food intake.
Avelox IV is for single use in one patient only. Discard any residue. Only clear solutions are to be used.
Store IV solution below 30°C. Do not store IV solution below 15°C. Do not refrigerate - product precipitates at temperatures below 15°C but will redissolve at room temperature (15°C - 25°C) (see Section 6.4 Special Precautions for Storage).
The solution should be inspected visually for particles prior to administration. Only clear solution free from particles should be used.

Compatible solutions for infusion.

Avelox IV is compatible with the following intravenous solutions at ratios from 1:10 to 10:1:
0.9% Sodium Chloride Injection USP;
1 M sodium chloride injection;
5% Glucose Injection USP;
Water for Injections USP;
10% Glucose for Injection USP;
glucose 40%;
lactated Ringer's solution for injection;
Ringer's solution;
xylitol 20%.
If the Y-type or "piggyback" method of administration is used, it is advisable to discontinue temporarily the administration of any other solutions during the infusion of Avelox IV.
Avelox IV is for single use in one patient only. Discard any residue. Only clear solutions are to be used.

Missed dose.

Film-coated tablet.

If a dose is missed, it should be taken anytime but not later than 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

Dose adjustments.

Elderly.

No adjustment of dose is necessary.

Paediatric.

The use of Avelox 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 Avelox in this patient group is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Use in severe hepatic impairment).

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.

4.3 Contraindications

Known hypersensitivity to any component of moxifloxacin or to any other quinolones or any of the excipients.
Because of an effect of moxifloxacin on the QTc interval of the electrocardiogram and a lack of clinical experience with the drug 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).
Also see Section 4.4 Special Warnings and Precautions for Use, General and 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 irreversible adverse reactions involving different body systems that have occurred together in the same patient. Patients of any age or without pre-existing risk factors have experienced these adverse reactions. These include, but are not limited to, serious adverse reactions involving the nervous system (see Section 4.4, Seizures and Peripheral neuropathy), musculoskeletal system (see Section 4.4, Tendonitis and tendon rupture) and psychiatric effects (see Section 4.4, Psychiatric reactions).

General.

The safety and effectiveness of Avelox 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 and 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 torsades 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 was observed in these studies.
No cardiovascular morbidity or mortality was attributed to moxifloxacin among over 5000 patients treated with oral Avelox, 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 Avelox. An additive effect of moxifloxacin and drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants cannot be excluded, therefore, Avelox should be used with caution when given concurrently with these drugs. 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.
Avelox 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 Avelox should be discontinued.

Seizures.

Seizures may occur with fluoroquinolone therapy. Avelox 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.

Avelox 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 Avelox. Avelox 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 drug and institute appropriate care.

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. Avelox 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 Avelox has to be discontinued, medical treatment (e.g. treatment for shock) is required.

Skin reactions.

Cases of bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with moxifloxacin (see Section 4.8 Adverse Effects (Undesirable Effects), Postmarketing 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 Avelox.

Dysglycaemia.

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported with Avelox. In Avelox 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.

Sodium content of solution for infusion.

In patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephrotic syndrome, etc.) the additional sodium load of the solution for infusion should be taken into account. The sodium content of the solution for infusion (250 mL) is 34 mmol.

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 Avelox.

Paediatric use.

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

Patients with severe hepatic impairment.

As limited clinical data are available in severe hepatic impairment (Child-Pugh C), the use of Avelox 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), Postmarketing 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.

Information for patients.

To assure safe and effective use of Avelox, the following information and instruction should be communicated to the patient when appropriate.
Patients should be advised:
that moxifloxacin may produce an effect on the electrocardiogram, and may add to the effect of other drugs 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 Avelox;
that Avelox tablets may be taken with or without meals and to drink fluids liberally;
that Avelox 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 drug 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 drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination;
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 drugs known to prolong the QT interval.

Antacids, minerals and multivitamins.

Concomitant ingestion of moxifloxacin together with antacids, minerals and multi-vitamins may result in impaired absorption of the drug 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 Avelox should be administered at least 2 hours before or four hours after ingestion of antacids and other preparations containing magnesium, aluminium, sucralfate and other minerals such as iron or zinc.

Antiretroviral drugs.

Oral doses of Avelox 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, 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 (C_max, T_max, 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 normalised 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 Avelox 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 C_max 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 C_max (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 (C_max 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 the drug 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%).

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 4.4 Special Warnings and Precautions for Use.)
There is limited information available on the potential for a pharmacodynamic interaction in humans between moxifloxacin and other drugs 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 drugs 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, Avelox 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).

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 0.2x 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 bodyweights, 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, bodyweight 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 Avelox, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

Avelox may cause dizziness and light-headedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery, or engage in activities requiring mental alertness or coordination.
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)).

4.8 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 in 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 ≥ 1/1,000 to < 1/100, rare ≥ 1/10,000 to < 1/1,000, 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).

Postmarketing adverse event reports.

Cardiovascular system disorders.

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

Hepatobiliary disorder.

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

Musculoskeletal, connective tissue and bone disorder.

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.

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. 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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Moxifloxacin is an 8-methoxyfluoroquinolone synthetic 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 in 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 sp., Bacteroides vulgatus, Enterococci and Klebsiella sp. 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 drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug 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. Avelox 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 pneumonia. Three large randomised, double blind controlled clinical studies were conducted to evaluate the efficacy of Avelox 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 (1,000 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 Avelox 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 US and Canada compared Avelox to an IV/PO fluoroquinolone control. Another study enrolled 628 patients from Europe, Israel and South Africa, and compared Avelox 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 Avelox therapy was equivalent to the fluoroquinolone comparators (86% vs 89%). The clinical success for Avelox therapy (93%) was higher than that for amoxicillin/ clavulanate ± clarithromycin (85%) (95% CI for the treatment difference was 2.9% to 13.2%).
The microbiological eradication rates (eradication plus presumed eradication) in Avelox treated patients from these two trials were Streptococcus pneumoniae 93% (63/68), Streptococcus pneumoniae bacteraemia 95% (19/20), Haemophilus influenzae 92% (23/25), Mycoplasma pneumoniae 96% (22/23) and Chlamydia pneumoniae 93% (13/14). Across all Avelox 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, Avelox 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, randomised, 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/PO moxifloxacin 400 mg qd versus piperacillin/ tazobactam 3.0/0.375 g IV followed by PO 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 (-12.04, +3.29 95% CI).
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 (-9.41, +2.18 95% CI).
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 prolongs 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, Avelox can be administered independent from meals.
The mean (± SD) C_max and AUC values following single and multiple doses of 400 mg moxifloxacin given orally or by 1 hour i.v. infusion are summarised in Table 10. (Also see Figure 1).

Plasma concentrations increase proportionately with dose up to the highest dose tested (1,200 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 (V_ss) 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 sulphate 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 sulphate 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/hr and 2.5 L/hr, 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, C_max 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 C_max 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 (Cl_Cr ≥ 30 and ≤ 60 mL/min) and severe (Cl_Cr < 30 mL/min) renal impairment. Mean AUC of the sulphate 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 severe hepatic impairment). 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 sulphate 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 Avelox 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.

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).

6 Pharmaceutical Particulars

6.1 List of Excipients

Avelox tablets also contain the following excipients: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, ferric oxide, hypromellose, macrogol 4000, and titanium dioxide.
Avelox IV contains the following excipients: sodium chloride, water for injections, may contain hydrochloric acid and/or sodium hydroxide for pH adjustment.

6.2 Incompatibilities

The following solutions for infusion must not be administered with Avelox solution for infusion: sodium chloride 10%, sodium chloride 20%, sodium hydrogen carbonate 4.2%, sodium hydrogen carbonate 8.4%.

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

Avelox 400 mg tablets should be stored below 25°C.
Avelox IV solution should be stored below 30°C. Do not store below 15°C. Do not refrigerate.

6.5 Nature and Contents of Container

Avelox tablets are packaged in blister strips in packs of 5 tablets and are available in one strength.
Avelox IV is available in ready-to-use 250 mL (containing 400 mg of moxifloxacin) polyolefine flexibags overwrapped with an aluminium bag or glass infusion bottles.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Moxifloxacin, a fluoroquinolone, differs from other quinolones in that it has a methoxy function at the 8-position and an S,S configurated diazabicyclononyl ring moiety at the 7-position. Its chemical name is 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-quinolinecarboxylic acid hydrochloride. It is a pale yellow substance. The substance shows no melting point but it decomposes above 250°C. It is sparingly soluble in water and methanol, slightly soluble in HCl and ethanol, and practicably insoluble in acetone and toluene. It has the following chemical structure:

Chemical structure.

Chemical Formula: C₂₁H₂₃FN₃O₄ * HCl.
Molecular Weight: 437.9.

CAS number.

CAS No: 186826-86-8.

7 Medicine Schedule (Poisons Standard)

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