MOFICIN

Composition

active substance: moxifloxacin;
1 bottle (250 ml of solution) contains 400 mg of moxifloxacin (in the form of moxifloxacin hydrochloride);
excipients: sodium chloride, anhydrous sodium sulfate, hydrochloric acid 1 N, sodium
hydroxide 1 N, water for injections.

Pharmaceutical form

Solution for infusion.
Main physical and chemical properties: clear, free of visible particles, greenish-yellow solution.

Pharmacotherapeutic group

Antibacterial agents for systemic use. Antibacterial agents of the quinolone group. ATC code: J01M А14.

Pharmacological properties

Pharmacodynamics.
Mechanism of action.
Moxifloxacin inhibits bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) that are required for bacterial DNA replication, transcription and repair.
Pharmacokinetics/pharmacodynamics.
The ability of fluoroquinolones to kill bacteria directly depends on their concentration. Pharmacodynamic studies of fluoroquinolones in animal models of infectious and inflammatory diseases and in humans show that the main determinant of efficacy is the ratio between the area under the pharmacokinetic curve (AUC₂₄) and the minimum inhibitory concentration (MIC).
Mechanism of resistance.
Resistance to fluoroquinolones can result from mutations in DNA gyrase and topoisomerase IV. Other mechanisms include overexpression of efflux pumps, impermeability and protein-mediated protection of DNA gyrase. Cross-resistance between moxifloxacin and other fluoroquinolones may be expected.
Resistance mechanisms characteristic of antibacterial agents belonging to other classes do not affect the antibacterial efficacy of moxifloxacin.
Breakpoints.
EUCAST (European Committee on Antimicrobial Susceptibility Testing) clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2012):

* Non-species related breakpoints have been determined mainly on the basis of pharmacokinetic / pharmacodynamic data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and are not for use with species where interpretative criteria remain to be determined.

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.
Commonly susceptible species.
Aerobic Gram-positive microorganisms: Staphylococcus aureus* ⁺, Streptococcus agalactiae (group B), Streptococcus milleri group* (S. anginosus, S. constellatus and S. intermedius), Streptococcus pneumoniae*, Streptococcus pyogenes* (group A), Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus).
Aerobic Gram-negative microorganisms: Acinetobacter baumanii, Haemophilus influenzae*, Legionella pneumophila, Moraxella (Branhamella) catarrhalis*.
Anaerobic microorganisms: Prevotella spp.
Other microorganisms: Chlamydophila (Chlamydia) pneumoniae*, Coxiella burnetii, Mycoplasma pneumoniae*.
Species in which resistance may develop.
Aerobic Gram-positive microorganisms: Enterococcus faecalis*, Enterococcus faecium*.
Aerobic Gram-negative microorganisms: Enterobacter cloacae*, Escherichia coli* ^#, Klebsiella pneumoniae* ^#, Klebsiella oxytoca, Proteus mirabilis*.
Anaerobic microorganisms: Bacteroides fragilis*.
Resistant microorganisms.
Aerobic Gram-negative microorganisms: Pseudomonas aeruginosa.
* Its effectiveness has been sufficiently demonstrated in clinical trials.
⁺ Methicillin resistant S. aureus have a high probability of resistance to fluoroquinolones. Moxifloxacin resistance rate of > 50% have been reported for methicillin resistant S. aureus.
^# ESBL-producing strains are commonly also resistant to fluoroquinolones.

Pharmacokinetics.
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 – 200 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 (V_ss) 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
Biotransformation
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.
No metabolic pharmacokinetic interactions with other drugs involved in phase I biotransformation, including cytochrome P 450 enzymes, were observed during in vitro and clinical phase I studies. There are no signs 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.
Renal impairment
The pharmacokinetic properties of moxifloxacin are not significantly different in patients with renal impairment (including creatinine clearance > 20 ml/min/1.73 m2). As renal function decreases, concentrations of the M2 metabolite (glucuronide) increase by up to a factor of 2.5 (with a creatinine clearance of < 30 ml/min/1.73 m2).
Hepatic impairment
On the basis of the pharmacokinetic studies carried out so far in patients with liver failure (Child-Pugh A, B), it is not possible to determine whether there are any differences compared with healthy volunteers. Impaired liver function was associated with higher exposure to M1 in plasma, whereas exposure to parent drug was comparable to exposure in healthy volunteers. There is insufficient experience in the clinical use of moxifloxacin in patients with impaired liver function.

Preclinical safety data
In conventional studies of repeated doses of moxifloxacin, haematological toxicity and hepatotoxicity in animals were observed. Toxic effects on the central nervous system (CNS) were observed. These effects were observed after administration of high doses of moxifloxacin or after prolonged use.
High oral doses in animals (≥ 60 mg/kg), against which the plasma concentration was ≥ 20 mg/l, caused changes in electroretinogram parameters and, in some cases, retinal atrophy.
After intravenous administration, systemic toxicity was most pronounced when moxifloxacin was administered by bolus injection (45 mg/kg) and was not observed when moxifloxacin (40 mg/kg) was administered by slow infusion over 50 minutes.
After intra-arterial administration, inflammatory changes were observed with spread to periarterial soft tissues, indicating that intra-arterial administration of moxifloxacin should be avoided.
Moxifloxacin was 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 animals.
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 animals at a dose of 30 mg/kg by infusion lasting 15, 30 or 60 minutes, the degree of QT prolongation depended on the infusion rate: the shorter the infusion time, the more pronounced the QT prolongation. QT prolongation was not observed when a dose of 30 mg/kg was administered by infusion for 60 minutes.
In the study of the effect of moxifloxacin on the reproductive function of animals, it was proved that moxifloxacin penetrates the placenta. Animal studies have not revealed any teratogenic effects of moxifloxacin or impaired fertility after its administration. In animals, a slight increase in the incidence of spinal and rib malformations was observed, but only at a dose (20 mg/kg intravenously) associated with severe maternal toxicity. An increase in the number of cases of pregnancy termination in animals was observed against the background of therapeutic plasma concentrations in humans.
Quinolones, including moxifloxacin, are known to cause cartilage damage to large diarthrodial joints in immature animals.

Therapeutic indications

• Community acquired pneumonia.
• Complicated skin and skin structure infections.

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.

Contraindications

• Hypersensitivity to moxifloxacin, other quinolones or to any of the excipients.
• Pregnancy and lactation (see section «Fertility, pregnancy and lactation»).
• Children’s age (up to 18 years).
• 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 «Interaction with other medicinal products and other forms of interaction»).
Due to insufficient clinical experience, moxifloxacin is contraindicated in patients with impaired liver function (Child-Pugh class C) and elevated transaminase levels five times or more.

Special warnings

The medicine bottle is intended for single use only. Any unused solution should be disposed of.
The following solutions have been found to be compatible with moxifloxacin 400 mg infusion solution: water for injection; sodium chloride solution 0.9%; sodium chloride solution 1-molar; glucose solution 5%, 10%, 40%; xylitol solution 20%; Ringer’s solution; complex solutions of sodium lactate (Hartmann’s solution, Ringer’s lactate solution).
Moxifloxacin infusion solution should not be administered in combination with other medicines.
Do not use the medicine in the presence of visible solid impurities or in case of solution turbidity.
If stored in a cool place, a precipitate may form, which dissolves at room temperature. Therefore, it is not recommended to store the infusion solution at temperatures below 15°C.

Interaction with other medicinal products and other forms of interaction

Interactions with medicinal products
An additive effect on QT interval prolongation of moxifloxacin and other medicinal products that may prolong the QTc interval cannot be excluded. This might lead to an increased risk of ventricular arrhythmias, including torsade de pointes. Therefore, co-administration of moxifloxacin with any of the following medicinal products is contraindicated (see also section «Contraindications»):
– 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 (e.g. loop and thiazide-type diuretics, laxatives and enemas [high doses], corticosteroids, amphotericin B) 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 (international normalised ratio).
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 supported 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.

Precautions for use

The use of moxifloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section «Undesirable effects»). Treatment of these patients with moxifloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section «Contraindications»).
The benefit of moxifloxacin treatment especially in infections with a low degree of severity should be balanced with the information contained in this section.
Prolongation of QT_с interval and potentially QT_с-prolongation-related clinical conditions
Moxifloxacin has been shown to prolong the QTc interval on the electrocardiogram in some patients. The magnitude of QT prolongation may increase with increasing plasma concentrations due to rapid intravenous infusion. Therefore, the duration of infusion should not be less than the recommended 60 minutes and the intravenous dose of 400 mg once a day should not be exceeded. For more details see sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction».
Moxifloxacin therapy should be discontinued in case of symptoms that may be associated with cardiac arrhythmia, regardless of whether this is confirmed by ECG findings.
Moxifloxacin should be used with caution in patients with conditions predisposing to arrhythmia (e.g. acute myocardial ischaemia), as such patients are at increased risk of ventricular arrhythmia (including polymorphic ventricular tachycardia of the pirouette type) and cardiac arrest (see also sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction»). Moxifloxacin should be administered with caution to patients taking medicinal products that may reduce potassium levels (see also sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction»).
Moxifloxacin should be administered with caution to patients receiving medicinal products associated with clinically significant bradycardia (see also section «Contraindications»).
Female patients and elderly patients may be more sensitive to the effects of QT_с-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 cases of clinical manifestations of severe hypersensitivity reactions 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 «Undesirable effects»). 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.
Severe skin reactions
Severe skin reactions, including toxic epidermal necrolysis (TEN, also known as Lyell’s syndrome), Stevens-Johnson syndrome (SJS) and acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with moxifloxacin (see section «Undesirable effects»). When prescribing the medicine, patients should be warned about the signs and symptoms of severe skin reactions and closely monitored. If symptoms suggestive of such reactions occur, moxifloxacin should be discontinued immediately and alternative treatment should be considered. If a patient develops severe skin reactions, such as SJS, TEN or AGEP, during treatment with moxifloxacin, treatment with moxifloxacin must not be restarted in this patient at any time.
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.
Prolonged, disabling and potentially irreversible serious adverse reactions
Rare cases of prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, mental and sensory) have been reported in patients treated with quinolones and fluoroquinolones, regardless of the patient’s age and risk factors. Moxifloxacin should be discontinued immediately upon development of the first symptoms of any serious adverse reaction, and patients should be advised to seek medical consultation.
Peripheral neuropathy
Cases of sensory or sensorimotor peripheral neuropathy resulting in paresthesia, hypoesthesia, dysesthesia or weakness have been reported in patients taking fluoroquinolones, including moxifloxacin. Moxifloxacin should be discontinued if the patient develops symptoms of neuropathy, such as pain, burning sensation, tingling, numbness or weakness, to prevent the development of a potentially irreversible condition (see section «Undesirable effects»).
Psychiatric reactions
Psychiatric reactions may occur even after the first use of fluoroquinolones, including moxifloxacin. In rare cases, depression or psychiatric reactions have progressed to suicidal ideation and manifestations of self-aggression such as suicide attempts (see section «Undesirable effects»). If a patient develops such reactions, treatment with moxifloxacin should be discontinued and appropriate measures should be taken. Caution should be exercised when administering moxifloxacin to patients with a current or previous history of psychiatric illness.
Antibiotic-associated diarrhoea incl. colitis
Cases of antibiotic-associated diarrhoea (AAD) and antibiotic-associated colitis (AAC), including pseudomembranous colitis and Clostridium difficile-associated diarrhoea, have been reported in connection with the use of broad-spectrum antibiotics, including moxifloxacin. The degree of manifestation of these phenomena can range from mild diarrhoea to fatal colitis. Therefore, it is important to consider the possibility of such a diagnosis in patients who develop severe diarrhoea during or after moxifloxacin administration. In case of suspected or confirmed AAD or AAC, treatment with antimicrobial agents, including moxifloxacin, should be discontinued and appropriate therapeutic measures should be initiated immediately. In addition, appropriate infection control measures should be taken to reduce the risk of transmission. Drugs inhibiting peristalsis are contraindicated in patients who develop serious diarrhoea.
Patients with severe myasthenia gravis
Moxifloxacin should be used with caution in patients with severe myasthenia gravis because the symptoms can be exacerbated.
Tendinitis and tendon rupture
In rare cases, patients may develop tendonitis. Tendonitis and tendon rupture (in particular of the Achilles tendon), sometimes on both sides, may occur within the first 48 hours after starting treatment with quinolones or fluoroquinolones, and such cases have been reported even several months after discontinuation of treatment. The risk of tendonitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients who have undergone parenchymal organ transplantation, and patients who are concomitantly treated with corticosteroids. Accordingly, concomitant use of corticosteroids should be avoided.
At the first signs of tendonitis (e.g. painful swelling, inflammation), moxifloxacin should be discontinued immediately and alternative treatment options should be considered. The affected limbs should be treated appropriately (e.g. by immobilising the tendon). In the presence of signs of tendinopathy, corticosteroids are not recommended.
Aortic aneurysm and aortic wall dissection, heart valve regurgitation/insufficiency
Epidemiological studies indicate an increased risk of aortic aneurysm and dissection, especially in elderly patients, and aortic and mitral valve regurgitation after fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatalities), and regurgitation/insufficiency of any of the heart valves have been reported in patients treated with fluoroquinolones (see section «Undesirable effects»).
Therefore, fluoroquinolones should be used after careful assessment of the benefit/risk ratio and after consideration of other therapeutic options in patients with a family history of aneurysm or congenital heart valve disease and patients with a diagnosis of aortic aneurysm or dissection or heart valve disease, or in the presence of other risk factors, namely:
– risk factors for the development of both aortic aneurysm and dissection and heart valve regurgitation/insufficiency: connective tissue diseases such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet’s disease, hypertension, rheumatoid arthritis;
– risk factors for aneurysm and aortic dissection: vascular disorders, such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjogren’s syndrome;
– risk factors for heart valve regurgitation/insufficiency: infective endocarditis.
The risk of aortic aneurysm and dissection and aortic rupture is increased in patients receiving systemic corticosteroids.
In the event of sudden abdominal pain, chest pain or back pain, patients should be advised to seek immediate medical attention in the emergency department.
Patients should be advised to seek immediate medical attention in case of acute shortness of breath, new onset of palpitations, or development of abdominal or lower extremity swelling.
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 «Effects on ability to drive and use machines» and «Undesirable effects»).
Dysglycemia
As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with moxifloxacin (see section «Undesirable effects»). In moxifloxacin-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g. sulfonylurea) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.
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
In patients with latent or detected glucose-6-phosphate dehydrogenase deficiency, quinolones can lead to haemolytic reactions during treatment with quinolone antibacterial agents, so moxifloxacin should be used with caution, monitoring the patient’s condition for possible haemolysis.
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 complicated skin and skin structure infections (cSSSI)
Clinical efficacy of moxifloxacin in the treatment of severe burn infections, fasciitis and diabetic foot infections with osteomyelitis has not been established.
Interference with biological tests
Moxifloxacin therapy may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth causing false negative results in samples taken from patients currently receiving moxifloxacin.
Patients with MRSA (methicillin-resistant Staphylococcus aureus) 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 «Pharmacodynamics»).
Important information about excipients.
This medicinal product contains 1072 mg (approximately 46.6 mmol) of sodium per dose (1 bottle). Caution should be exercised when using the medicinal product in patients on a sodium-controlled diet.

Fertility, pregnancy and lactation.
Pregnancy
The safety of moxifloxacin during pregnancy in humans has not been studied. The results of animal studies indicate reproductive toxicity (see section «Pharmacological properties»). The potential risk to humans has not been established. Taking into account the experimentally established risk of harmful effects of fluoroquinolones on cartilage bearing the main load in immature animals and taking into account the development of reversible joint lesions in children treated with some fluoroquinolones, moxifloxacin should not be prescribed to pregnant women (see section «Contraindications»).
Breast-feeding
There are no data on the use of the medicine during breastfeeding in women. The results of preclinical studies indicate that a small amount of moxifloxacin passes into breast milk. Due to the lack of data on the effect on infants fed with breast milk and taking into account the experimental risk of harmful effects of fluoroquinolone on cartilage of immature animals that bear the main load, breastfeeding is contraindicated during treatment with moxifloxacin (see section «Contraindications»).
Fertility
Animal studies do not indicate impairment of fertility (see section «Pharmacological properties»).

Effects on ability to drive and use machines.
No studies have been conducted on the effect of moxifloxacin on the ability to drive or use machinery. However, fluoroquinolones, including moxifloxacin, can affect the speed of reaction when driving or working with other machinery, causing central nervous system reactions (e.g. dizziness, acute temporary loss of vision) or acute and short-term loss of consciousness (fainting) (see section «Undesirable effects»). Patients are advised to check their reaction to moxifloxacin before driving or operating other machinery.

Posology and method of administration

Posology
The recommended dosage regimen is 400 mg of moxifloxacin as an infusion once daily.
Initial intravenous therapy may be continued with oral administration of moxifloxacin 400 mg tablets if clinically indicated.
In clinical trials, the majority of patients switched to oral moxifloxacin within 4 days (community-acquired pneumonia) or 6 days (complicated skin and subcutaneous tissue infections). The recommended total duration of intravenous and oral treatment is 7-14 days for community-acquired pneumonia and 7-21 days for complicated skin and subcutaneous tissue infections.
Method of administration
The medicine should be administered intravenously as a continuous infusion lasting at least 60 minutes (also see section «Precautions for use»).
If indicated, the infusion solution can be administered through a T-catheter together with compatible infusion solutions (see section «Special warnings»).
Renal/hepatic impairment
Patients with mild to severe renal impairment and patients undergoing continuous outpatient peritoneal dialysis (CAPD), such as those undergoing haemodialysis and CAPD, do not require dose adjustment (see section «Pharmacological properties» for more details).
There is insufficient information regarding patients with hepatic impairment (see section «Contraindications»).
Other special populations
No adjustment of dosage is required in the elderly and in patients with low bodyweight.

Paediatric population.
Moxifloxacin is contraindicated in children and growing adolescents (see section «Pharmacological properties»). Moxifloxacin should not be given to children younger than 18 years old. (see section «Contraindications»). Efficacy and safety of moxifloxacin in children and adolescents have not been established (see section «Contraindications»).

Overdose

There are no recommendations for special measures after an accidental overdose. In case of an overdose, symptomatic treatment is provided. Since QT prolongation is possible, ECG monitoring is required. Simultaneous use of activated charcoal with a 400 mg dose of moxifloxacin administered orally or intravenously reduces the systemic bioavailability of the medicinal product by more than 80% or 20%, respectively. Intake of activated charcoal at the initial stage of absorption can be an effective prevention of excessive increase in systemic exposure of moxifloxacin in case of overdose after oral administration.

Undesirable effects

The following adverse reactions have been observed in clinical trials and in the post-marketing period with moxifloxacin 400 mg daily (intravenous therapy only, stepped [intravenous/oral] and oral). Adverse reactions are classified according to their frequency.
All adverse reactions, with the exception of nausea and diarrhoea, were observed with a frequency of less than 3%.
In each group, adverse events are listed in descending order of severity. Frequencies are defined as: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, ≤ 1/100), rare (≥ 1/10000, ≤ 1/1000), very rare ( ≤ 1/10000), not known (cannot be estimated from the available data).
Eye disorders*: uncommon – visual impairment, including diplopia and blurred vision (especially during reactions from the central nervous system) (see section «Precautions for use»); rare – photophobia; very rare – transient visual loss (especially during reactions from the central nervous system) (see sections «Precautions for use», «Effects on ability to drive and use machines»), uveitis and bilateral acute iris transillumination (see section «Precautions for use»).
Ear and labyrinth disorders*: rare – ringing in the ears, hearing impairment, including deafness (usually reversible);
Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea (including asthmatic conditions).
Gastrointestinal disorders: common – nausea, vomiting, gastrointestinal and abdominal pains, diarrhoea; uncommon – decreased appetite and decreased food intake, constipation, dyspepsia, flutillation, gastritis, increased amylase levels; rare – dysphagia, stomatitis, antibiotic-associated colitis (including pseudomembranous colitis, in very rare cases associated with life-threatening complications) (see section «Precautions for use»).
Hepatobiliary disorders: common – increased in transaminases; uncommon – hepatic impairment (including increased levels of LDH [lactate dehydrogenase]), increased levels of bilirubin, GGTP (gamma-glutamyl transpeptidase), alkaline phosphatase; rare – jaundice, hepatitis (predominantly cholestatic); very rare – fulminant hepatitis, which can lead to the development of life-threatening liver failure (see section «Precautions for use»).
Renal and urinary disorders: uncommon – dehydration; rare – renal impairment (including increased blood urea nitrogen and creatinine levels), renal failure (see section «Precautions for use»);
Endocrine disorders: very rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH);
Metabolism and nutrition disorders: uncommon – hyperlipidaemia; rare – hyperglycaemia, hyperuricaemia; very rare – hypoglycaemia, hypoglycaemic coma.
Nervous system disorders*: common – headache, dizziness; uncommon – paresthesia/dysesthesia, taste disturbance (including ageusia in very rare cases), confusion and disorientation, sleep disorders (predominantly insomnia), tremor, vertigo, somnolence; rare – hypoesthesia, smell disorders (incl. anosmia), abnormal dreams, disturbed coordination (incl. gait disturbances, esp. due to dizziness or vertigo), seizures (incl. grand mal convulsions) (see section «Precautions for use»), disturbed attention, speech disorder, amnesia, peripheral neuropathy and polyneuropathy; very rare – hyperesthesia.
Psychiatric disorders*: uncommon – anxiety reactions, psychomotor hyperactivity / agitation; rare – emotional lability, depression (in very rare cases potentially culminating in self-injurious behaviour, such as suicidal ideations / thoughts, or suicide attempts) (see section «Precautions for use»), hallucinations, delirium; very rare – depersonalisation, psychotic reactions (potentially culminating in self-injurious behaviour, such as suicidal ideations/ thoughts, or suicide attempts) (see section «Precautions for use»)
Cardiac disorders**: common – QT prolongation in patients with hypokalaemia (see sections «Contraindications», «Precautions for use»); uncommon – QT prolongation (see section «Precautions for use»), palpitations, tachycardia, atrial fibrillation, angina pectoris; rare – ventricular tachyarrhythmias, Syncope (i.e., acute and short lasting loss of consciousness); very rare – unspecified arrhythmias, pirouetted ventricular tachycardia (torsade de pointes) (see section «Precautions for use»), cardiac arrest (see section «Precautions for use»).
Vascular disorders**: uncommon – vasodilation; rare – arterial hypertension, hypotension, very rare – vasculitis.
Blood and lymphatic system disorders: uncommon – anaemia, leucopenia(s), neutropenia, thrombocytopenia, thrombocythemia, blood eosinophilia, prothrombin time prolonged / INR increased; very rare – prothrombin level increased / INR decreased, agranulocytosis, pancytopenia.
Immune system disorders : uncommon – allergic reactions (see section «Precautions for use»); rare – anaphylaxis, including in very rare cases life-threatening shock (see section «Precautions for use»), allergic edema / angioedema (including laryngeal edema, potentially life-threatening (see section «Precautions for use»).
Skin and subcutaneous tissue disorders: uncommon – pruritus, rash, urticaria, dry skin; very rare – bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (potentially life-threatening) (see section «Precautions for use»); not known – acute generalised exanthematous pustulosis (AGEP).
Musculoskeletal, connective tissue and bone disorders*: uncommon – arthralgia, myalgia; rare – tendonitis (see section «Precautions for use»), increased muscle tone, muscle cramps, muscle weakness; very rare – tendon rupture (see section «Precautions for use»), arthritis, muscle rigidity, exacerbation of symptoms myasthenia gravis (see section «Precautions for use»); not known – rhabdomyolysis.
General disorders and administration site conditions*: common – injection and infusion site reactions; uncommon – feeling unwell (predominantly asthenia or fatigue), painful conditions (including pain in back, chest, pelvic and extremities), excessive sweating, (thrombo-)phlebitis at the infusion site.
Infections and infestations: common – superinfections associated with resistant bacteria or fungi, such as oral and vaginal candidiasis.
* In very rare cases, patients treated with quinolones and fluoroquinolones, regardless of the presence of risk factors, have experienced prolonged (months or years), disabling and potentially irreversible serious adverse reactions, affecting various body systems and sensory organs (such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell).
** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section «Precautions for use»).

The following undesirable effects have a higher frequency category in the subgroup of IV treated patients with or without subsequent oral therapy.
Common: increased gamma-glutamyltransferase.
Uncommon: ventricular tachyarrhythmias, hypotension, oedema, antibiotic-associated colitis (incl. pseudomembranous colitis, in very rare cases associated with life-threatening complications, see section «Precautions for use»), seizures incl. grand mal convulsions (see section «Precautions for use»), hallucination, renal impairment (incl. increased blood urea nitrogen and creatinine levels), renal failure (see section «Precautions for use»).
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: increased intracranial pressure (including idiopathic intracranial hypertension), hypernatraemia, hypercalcaemia, haemolytic anaemia, photosensitivity reactions (see section «Precautions for use»).
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and the patients or their legal guardians/carers are asked to report any suspected adverse reactions via the State Expert Center of the Ministry of Health of Ukraine at the link: https://aisf.dec.gov.ua/

Shelf life

4 years.

Storage conditions

Store in the original packaging at a temperature not lower than 15 °C.
Do not refrigerate. Do not freeze. Keep out of the reach of children.

Incompatibilities

Moxifloxacin infusion solution should not be administered simultaneously with other incompatible solutions, which include: sodium chloride solution 10%; sodium chloride solution 20%; sodium bicarbonate solution 4.2%; sodium bicarbonate solution 8.4%.
This medicinal product should not be mixed with any other medicines except those listed in the section «Special warnings».

Packaging

250 ml of solution in bottles. 1 bottle in a cardboard box.

Prescription status

Available on prescription.

Manufacturer

ANFARM HELLAS S.A.

Manufacturer’s location and address of the place of operation
61st km NAT.RD. ATHENS-LAMIA, Schimatari Viotias, 32009, Greece.

Applicant

TEKHNOPAK MANUFACTURE LIMITED.

Applicant ‘s location

Office 4, Unit 1, North Park, Finglas, Dublin, D11 E6C3, Ireland.