Avelox 400 mg/250 ml solution for infusion

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

1 ml contains 1.6 mg moxifloxacin (as hydrochloride).

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

For a full list of excipients, see section 6.1.

Solution for infusion

Clear, yellow solution

Avelox is indicated for the treatment of:

- Community acquired pneumonia (CAP)

- Complicated skin and skin structure infections (cSSSI)

Moxifloxacin should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

400 mg moxifloxacin, infused once daily.

Initial intravenous treatment may be followed by oral treatment with moxifloxacin 400 mg tablets, when clinically indicated.

In clinical studies most patients switched to oral therapy within 4 days (CAP) or 6 days (cSSSI). The recommended total duration of intravenous and oral treatment is 7 - 14 days for CAP and 7 - 21 days for cSSSI.

Renal/hepatic impairment

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

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

Other special populations

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

Children and adolescents

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

Method of administration

For intravenous use; constant infusion over 60 minutes (see also section 4.4).

If medically indicated the solution for infusion can be administered via a T-tube, together with compatible infusion solutions (see section 6.6).

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

- Pregnancy and lactation (see section 4.6).

- Patients below 18 years of age.

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

Both in preclinical investigations and in humans, changes in cardiac electrophysiology have been observed following exposure to moxifloxacin, in the form of QT prolongation. For reasons of drug safety, moxifloxacin is therefore contraindicated in patients with:

- Congenital or documented acquired QT prolongation

- Electrolyte disturbances, particularly in uncorrected hypokalaemia

- Clinically relevant bradycardia

- Clinically relevant heart failure with reduced left-ventricular ejection fraction

- Previous history of symptomatic arrhythmias

Moxifloxacin should not be used concurrently with other drugs that prolong the QT interval (see also section 4.5).

Due to limited clinical data, moxifloxacin is also contraindicated in patients with impaired liver function (Child Pugh C) and in patients with transaminases increase > 5fold ULN.

The benefit of moxifloxacin treatment especially in infections with a low degree of severity should be balanced with the information contained in the warnings and precautions section.

Prolongation of QTc interval and potentially QTc-prolongation-related clinical conditions

Treatment with moxifloxacin should be stopped if signs or symptoms that may be associated with cardiac arrhythmia occur during treatment, with or without ECG findings.

Moxifloxacin should be used with caution in patients with any condition pre-disposing to cardiac arrhythmias (e.g. acute myocardial ischaemia) because they may have an increased risk of developing ventricular arrhythmias (incl. torsade de pointes) and cardiac arrest. See also sections 4.3 and 4.5.

Moxifloxacin should be used with caution in patients who are taking medications that can reduce potassium levels. See also section 4.3.

Moxifloxacin should be used with caution in patients who are taking medications associated with clinically significant bradycardia. See also section 4.3.

Female patients and elderly patients may be more sensitive to the effects of QTc-prolonging medications such as moxifloxacin and therefore special caution is required.

Hypersensitivity / allergic reactions

Hypersensitivity and allergic reactions have been reported for fluoroquinolones including moxifloxacin after first administration. Anaphylactic reactions can progress to a life-threatening shock, even after the first administration. In these cases moxifloxacin should be discontinued and suitable treatment (e.g. treatment for shock) initiated.

Severe liver disorders

Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported with moxifloxacin (see section 4.8). Patients should be advised to contact their doctor prior to continuing treatment if signs and symptoms of fulminant hepatic disease develop such as rapidly developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy.

Liver function tests/investigations should be performed in cases where indications of liver dysfunction occur.

Serious bullous skin reactions

Cases of bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with moxifloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.

Patients predisposed to seizures

Quinolones are known to trigger seizures. Use should be with caution in patients with CNS disorders or in the presence of other risk factors which may predispose to seizures or lower the seizure threshold. In case of seizures, treatment with moxifloxacin should be discontinued and appropriate measures instituted.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesias, hypoaesthesias, dysaesthesias, or weakness have been reported in patients receiving quinolones. Patients under treatment with moxifloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop (see section 4.8).

Psychiatric reactions

Psychiatric reactions may occur even after the first administration of quinolones, including moxifloxacin. In very rare cases depression or psychotic reactions have progressed to suicidal thoughts and self-endangering behaviour such as suicide attempts (see section 4.8). In the event that the patient develops these reactions, moxifloxacin should be discontinued and appropriate measures instituted. Caution is recommended if moxifloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.

Antibiotic-associated diarrhoea incl. colitis

Antibiotic-associated diarrhoea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, has been reported in association with the use of broad spectrum antibiotics including moxifloxacin and may range in severity from mild diarrhoea to fatal colitis. Therefore it is important to consider this diagnosis in patients who develop serious diarrhoea during or after the use of moxifloxacin. If AAD or AAC is suspected or confirmed, ongoing treatment with antibacterial agents, including moxifloxacin, should be discontinued and adequate therapeutic measures should be initiated immediately. Furthermore, appropriate infection control measures should be undertaken to reduce the risk of transmission. Drugs inhibiting peristalsis are contraindicated in patients who develop serious diarrhoea.

Patients with myasthenia gravis

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

Tendon inflammation, tendon rupture

Tendon inflammation and rupture (especially Achilles tendon), sometimes bilateral, may occur with quinolone therapy including moxifloxacin, even within 48 hours of starting treatment and have been reported up to several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue treatment with moxifloxacin, rest the affected limb(s) and consult their doctor immediately in order to initiate appropriate treatment (e.g. immobilisation) for the affected tendon (see sections 4.3 and 4.8).

Patients with renal impairment

Elderly patients with renal disorders should use moxifloxacin with caution if they are unable to maintain adequate fluid intake, because dehydration may increase the risk of renal failure.

Vision disorders

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).

Prevention of photosensitivity reactions

Quinolones have been shown to cause photosensitivity reactions in patients. However, studies have shown that moxifloxacin has a lower risk to induce photosensitivity. Nevertheless patients should be advised to avoid exposure to either UV irradiation or extensive and/or strong sunlight during treatment with moxifloxacin.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with a family history of or actual glucose-6-phosphate dehydrogenase deficiency are prone to haemolytic reactions when treated with quinolones. Therefore, moxifloxacin should be used with caution in these patients.

Peri-arterial tissue inflammation

Moxifloxacin solution for infusion is for intravenous administration only. Intra-arterial administration should be avoided since preclinical studies demonstrated peri-arterial tissue inflammation following infusion by this route.

Patients with special cSSSI

Clinical efficacy of moxifloxacin in the treatment of severe burn infections, fasciitis and diabetic foot infections with osteomyelitis has not been established.

Patients on sodium diet

This medicinal product contains 787 mg (approximately 34 mmol) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

Interference with biological tests

Moxifloxacin therapy may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth causing false negative results.

Patients with MRSA infections

Moxifloxacin is not recommended for the treatment of MRSA infections. In case of a suspected or confirmed infection due to MRSA, treatment with an appropriate antibacterial agent should be started (see section 5.1).

Paediatric population

Due to adverse effects on the cartilage in juvenile animals (see section 5.3) the use of moxifloxacin in children and adolescents < 18 years is contraindicated (see section 4.3).

Interactions with medicinal products

An additive effect on QT interval prolongation of moxifloxacin and other medicinal products that may prolong the QTc interval cannot be excluded. This might lead to an increased risk of ventricular arrhythmias, including torsade de pointes. Therefore, co-administration of moxifloxacin with any of the following medicinal products is contraindicated (see also section 4.3):

- anti-arrhythmics class IA (e.g. quinidine, hydroquinidine, disopyramide)

- anti-arrhythmics class III (e.g. amiodarone, sotalol, dofetilide, ibutilide)

- antipsychotics (e.g. phenothiazines, pimozide, sertindole, haloperidol, sultopride)

- tricyclic antidepressive agents

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

- certain antihistaminics (terfenadine, astemizole, mizolastine)

- others (cisapride, vincamine IV, bepridil, diphemanil).

Moxifloxacin should be used with caution in patients who are taking medication that can reduce potassium levels or medication that is associated with clinically significant bradycardia.

After repeated dosing in healthy volunteers, moxifloxacin increased C_max of digoxin by approximately 30% without affecting AUC or trough levels. No precaution is required for use with digoxin.

In studies conducted in diabetic volunteers, concomitant administration of oral moxifloxacin with glibenclamide resulted in a decrease of approximately 21% in the peak plasma concentrations of glibenclamide. The combination of glibenclamide and moxifloxacin could theoretically result in a mild and transient hyperglycaemia. However, the observed pharmacokinetic changes for glibenclamide did not result in changes of the pharmacodynamic parameters (blood glucose, insulin). Therefore no clinically relevant interaction was observed between moxifloxacin and glibenclamide.

Changes in INR

A large number of cases showing an increase in oral anticoagulant activity have been reported in patients receiving antibacterial agents, especially fluoroquinolones, macrolides, tetracyclines, cotrimoxazole and some cephalosporins. The infectious and inflammatory conditions, age and general status of the patient appear to be risk factors. Under these circumstances, it is difficult to evaluate whether the infection or the treatment caused the INR (international normalised ratio) disorder. A precautionary measure would be to more frequently monitor the INR. If necessary, the oral anticoagulant dosage should be adjusted as appropriate.

Clinical studies have shown no interactions following concomitant administration of moxifloxacin with: ranitidine, probenecid, oral contraceptives, calcium supplements, morphine administered parenterally, theophylline, cyclosporine or itraconazole.

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

Interaction with food

Moxifloxacin has no clinically relevant interaction with food including dairy products.

Pregnancy

The safety of moxifloxacin in human pregnancy has not been evaluated. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of immature animals and reversible joint injuries described in children receiving some fluoroquinolones, moxifloxacin must not be used in pregnant women (see section 4.3).

Lactation

There is no data available in lactating or nursing women. Preclinical data indicate that small amounts of moxifloxacin are secreted in milk. In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of immature animals, breast-feeding is contraindicated during moxifloxacin therapy (see section 4.3).

No studies on the effects of moxifloxacin on the ability to drive and use machines have been performed. However, fluoroquinolones including moxifloxacin may result in an impairment of the patient's ability to drive or operate machinery due to CNS reactions (e.g. dizziness; acute, transient loss of vision, see section 4.8) or acute and short lasting loss of consciousness (syncope, see section 4.8). Patients should be advised to see how they react to moxifloxacin before driving or operating machinery.

Adverse reactions observed in clinical trials with moxifloxacin 400 mg daily administered by the intravenous or oral route sorted by frequencies are listed below:

Apart from nausea and diarrhoea all adverse reactions were observed at frequencies below 3%.

The following undesirable effects have a higher frequency category in the subgroup of IV treated patients with or without subsequent oral therapy:

There have been very rare cases of the following side effects reported following treatment with other fluoroquinolones, which might possibly also occur during treatment with moxifloxacin: hypernatraemia, hypercalcaemia, haemolytic anaemia, rhabdomyolysis, photosensitivity reactions, peripheral neuropathy (see section 4.4).

No specific countermeasures after accidental overdose are recommended. In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Concomitant administration of charcoal with a dose of 400 mg oral or intravenous moxifloxacin will reduce systemic availability of the drug by more than 80% or 20% respectively. The use of charcoal early during absorption may be useful to prevent excessive increase in the systemic exposure to moxifloxacin in cases of oral overdose.

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

Mode of action

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

PK/PD

Fluoroquinolones exhibit a concentration dependent killing of bacteria. Pharmacodynamic studies of fluoroquinolones in animal infection models and in human trials indicate that the primary determinant of efficacy is the AUC₂₄/MIC ratio.

Mechanism of resistance

Resistance to fluoroquinolones can arise through mutations in DNA gyrase and topoisomerase IV. Other mechanisms may include over-expression of efflux pumps, impermeability, and protein-mediated protection of DNA gyrase. Cross resistance should be expected between moxifloxacin and other fluoroquinolones.

The activity of moxifloxacin is not affected by mechanisms of resistance that are specific to antibacterial agents of other classes.

Breakpoints

EUCAST clinical MIC breakpoints for moxifloxacin (31.01.2006):

Microbiological Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent in at least some types of infections is questionable.

Absorption and Bioavailability

After a single 400 mg intravenous 1 hour infusion peak plasma concentrations of approximately 4.1 mg/l were observed at the end of the infusion corresponding to a mean increase of approximately 26% relative to those seen after oral administration (3.1 mg/l). The AUC value of approximately 39 mg∙h/l after i.v. administration is only slightly higher than that observed after oral administration (35 mg∙h/l) in accordance with the absolute bioavailability of approximately 91%.

In patients, there is no need for age or gender related dose adjustment on intravenous moxifloxacin.

Pharmacokinetics are linear in the range of 50 - 1200 mg single oral dose, up to 600 mg single intravenous dose and up to 600 mg once daily dosing over 10 days.

Distribution

Moxifloxacin is distributed to extravascular spaces rapidly. The steady-state volume of distribution (Vss) is approximately 2 l/kg. In vitro and ex vivo experiments showed a protein binding of approximately 40 - 42% independent of the concentration of the drug. Moxifloxacin is mainly bound to serum albumin.

Maximum concentrations of 5.4 mg/kg and 20.7 mg/l (geometric mean) were reached in bronchial mucosa and epithelial lining fluid, respectively, 2.2 h after an oral dose. The corresponding peak concentration in alveolar macrophages amounted to 56.7 mg/kg. In skin blister fluid concentrations of 1.75 mg/l were observed 10 h after intravenous administration. In the interstitial fluid unbound concentration time profiles similar to those in plasma were found with unbound peak concentrations of 1.0 mg/l (geometric mean) reached approximately 1.8 h after an intravenous dose.

Metabolism

Moxifloxacin undergoes Phase II biotransformation and is excreted via renal (approximately 40%) and biliary/faecal (approximately 60%) pathways as unchanged drug as well as in the form of a sulpho-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive.

In clinical Phase I and in vitro studies no metabolic pharmacokinetic interactions with other drugs undergoing Phase I biotransformation involving cytochrome P450 enzymes were observed. There is no indication of oxidative metabolism.

Elimination

Moxifloxacin is eliminated from plasma with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 ml/min. Following a 400 mg intravenous infusion recovery of unchanged drug from urine was approximately 22% and from faeces approximately 26%. Recovery of the dose (unchanged drug and metabolites) totalled to approximately 98% after intravenous administration of the drug. Renal clearance amounted to about 24 - 53 ml/min suggesting partial tubular reabsorption of the drug from the kidneys. Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.

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

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

In conventional repeated dose studies moxifloxacin revealed haematological and hepatic toxicity in rodents and non-rodents. Toxic effects on the CNS were observed in monkeys. These effects occurred after the administration of high doses of moxifloxacin or after prolonged treatment.

In dogs, high oral doses ( 60 mg/kg) leading to plasma concentrations 20 mg/l caused changes in the electroretinogram and in isolated cases an atrophy of the retina.

After intravenous administration findings indicative of systemic toxicity were most pronounced when moxifloxacin was given by bolus injection (45 mg/kg) but they were not observed when moxifloxacin (40 mg/kg) was given as slow infusion over 50 minutes.

After intra-arterial injection inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.

Moxifloxacinwas genotoxic in in vitro tests using bacteria or mammalian cells. In in vivo tests, no evidence of genotoxicity was found despite the fact that very high moxifloxacin doses were used. Moxifloxacin was non-carcinogenic in an initiation-promotion study in rats.

In vitro, moxifloxacin revealed cardiac electrophysiological properties that can cause prolongation of the QT interval, even though at high concentrations.

After intravenous administration of moxifloxacin to dogs (30 mg/kg infused over 15, 30 or 60 minutes) the degree of QT prolongation was clearly depending on the infusion rate, i.e. the shorter the infusion time the more pronounced the prolongation of the QT interval. No prolongation of the QT interval was seen when a dose of 30 mg/kg was infused over 60 minutes.

Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in rats (p.o. and i.v.) and monkeys (p.o.) did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. A slightly increased incidence of vertebral and rib malformations was observed in foetuses of rabbits but only at a dose (20 mg/kg i.v.) which was associated with severe maternal toxicity. There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic plasma concentrations.

Quinolones, including moxifloxacin, are known to cause lesions in the cartilage of the major diarthrodial joints in immature animals.

Sodium chloride

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

Water for injections

The following solutions are incompatible with moxifloxacin solution for infusion:

Sodium chloride 10% and 20% solutions

Sodium bicarbonate 4.2% and 8.4% solutions

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Use immediately after first opening and/or dilution.

Do not store below 15°C.

Polyolefine bags with polypropylene port sealed in aluminium foil overwrap. 250 ml pack available in cartons of 5 and 12 bags.

Colourless glass bottles (type 2) with a chlorobutyl or bromobutyl rubber stopper as closure. The 250 ml bottle is available in packs of 1 and 5 bottles.

Not all pack sizes may be marketed.

This product is for single use only. Any unused solution should be discarded.

The following co-infusions were found to be compatible with moxifloxacin 400 mg solution for infusion:

Water for injections, Sodium chloride 0.9%, Sodium chloride 1 molar, Glucose 5%/10%/40%, Xylitol 20%, Ringer's solution, Compound Sodium Lactate Solution (Hartmann's Solution, Ringer-Lactate Solution).

Moxifloxacin solution for infusion should not be co-infused with other drugs.

Do not use if there are any visible particulate matter or if the solution is cloudy.

At cool storage temperatures precipitation may occur, which will re-dissolve at room temperature. It is therefore recommended not to store the infusion solution below 15°C.

Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom.

PL 00010/0613

First authorisation: 12^th November 2009

11 November 2011