Avelox

Moxifloxacin hydrochloride.

Each film-coated tablet contains: Moxifloxacin (as hydrochloride) 400 mg.
List of excipients: Excipients: Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose. Film-Coating: ferric oxide red, hypromellose 15 cP, macrogol 4000, titanium dioxide.

Pharmacology: Pharmacodynamics: Mechanism of action: Moxifloxacin is a 8-methoxy-fluoroquinolone antibiotic with a broad spectrum of activity and bactericidal action. Moxifloxacin has in vitro activity against a wide range of gram-positive and gram-negative organisms, anaerobes, acid-fast bacteria, and atypicals e.g. Chlamydia spp., Mycoplasma spp. and Legionella spp.
The bactericidal action results from the interference with topoisomerase II and IV. Topoisomerases are essential enzymes which control DNA topology and assist in DNA replication, repair and transcription.
Moxifloxacin exhibits concentration dependent bactericidal killing. Minimum bactericidal concentrations are generally similar to minimum inhibitory concentrations.
Moxifloxacin is effective against β-lactam and macrolide resistant bacteria. Studies in animal models of infection have demonstrated high in vivo activity.
Resistance: Resistance mechanisms which inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. There is no cross resistance between moxifloxacin and these agents. Plasmid-mediated resistance has not been observed to date.
It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, a mechanism of fluoroquinolone resistance.
In vitro studies have demonstrated that resistance to moxifloxacin develops slowly by multiple step mutations. A very low overall frequency of resistance was demonstrated (10^-7 - 10^-10). Serial exposure of organisms to sub-MIC concentrations of moxifloxacin showed only a small increase in MIC values.
Cross resistance among fluoroquinolones has been observed. However, some gram-positive and anaerobic organisms resistant to other fluoroquinolones are susceptible to moxifloxacin.
Effect on the intestinal flora in humans: In two volunteer studies, the following changes in the intestinal flora were seen following oral dosing with moxifloxacin. E. coli, Bacillus spp., Bacteroides vulgatus, Enterococci, and Klebsiella spp. were reduced, as were the anaerobes Bifidobacterium, Eubacterium, and Peptostreptococcus. These changes returned to normal within two weeks. Clostridium difficile toxin was not found.
In vitro Susceptibility Data: See Table 1.

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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. The previously mentioned information is provided as a guide on the probability of an organism being susceptible to moxifloxacin.
Comparison of PK/PD surrogates for intravenous and oral administration of a 400 mg Moxifloxacin (Avelox) single dose.
In patients requiring hospitalization AUC/MIC₉₀ parameters greater than 125 and C_max/MIC₉₀ of 8 - 10 is predictive for clinical cure (Schentag). In outpatients these surrogate parameters are generally smaller, i.e. AUC/MIC₉₀ greater than 30 - 40 (Dudley and Ambrose).
The following table provides the respective PK/PD surrogates for intravenous and oral administration of 400 mg moxifloxacin calculated from single dose data: See Table 2.

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Special patient population: Pediatric Patients: Clinical study in complicated intra-abdominal infection (cIAI): The safety of moxifloxacin in pediatric patients 3 months to <18 years of age (mean age of 12 ± 4 years) was investigated in one randomized, double-blind, active controlled trial in cIAI including appendicitis with perforation, abscesses and peritonitis. Efficacy was investigated as a secondary objective. Patients received sequential intravenous/oral moxifloxacin or intravenous ertapenem followed by oral amoxicillin/clavulanate for 5 to 14 days (mean duration was 9 days with a range of 1 to 24 days) as shown in the table as follows. (See Table 3.)

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The primary objective of the trial was to assess the safety of moxifloxacin with a focus on cardiac and musculoskeletal safety. This study enrolled 458 patients, 301 of which were treated with moxifloxacin, 150 with active control and 7 patients did not receive study treatment.
Adverse events were reported in more than half of all patients in both treatment groups. The incidence of patients experiencing at least one adverse event was similar between the treatment groups. The most frequently occurring adverse events with moxifloxacin were QT prolongation, diarrhea and phlebitis. No cardiovascular morbidity or mortality attributable to QT prolongation occurred with moxifloxacin. Discontinuation of study drug due to an adverse event was reported in 5.3% (16/301) of moxifloxacin-treated patients versus 1.3% (2/150) of comparator patients. The adverse event profile of moxifloxacin or comparator was similar across all age groups studied.
The rates of musculoskeletal events were 4.3% (13/301) in the moxifloxacin-treated group versus 3.3% (5/150) in comparator-treated patients. The majority of musculoskeletal events were reported between 12 and 53 weeks after start of study treatment, and all events resolved (clinical resolution of signs and symptoms) at the end of the study.
A secondary endpoint of the trial was to assess the clinical and bacteriological response at the test-of-cure visit. The clinical and bacteriological responses in children treated with moxifloxacin were within the range of that observed in adults with cIAI (see Dosage & Administration).
Descriptive analysis of the overall clinical success at the test-of-cure visit (28 to 42 days after end of treatment) in all patients treated with study drug (safety population) is shown in the table as follows. (See Table 4.)

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Safety of moxifloxacin after single dose application: The safety and tolerability of moxifloxacin was investigated in pediatric patients 3 months to ≤14 years of age (mean age of 5 ± 4 years) in one non-randomized, non-blinded, uncontrolled, multicenter trial. The trial was designed to evaluate the pharmacokinetics of moxifloxacin. A total of 31 patients received moxifloxacin as an 1-hour intravenous infusion at different doses as shown in the table as follows. (See Table 5.)

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For results of pharmacokinetics, see Pharmacokinetics as follows. Adverse events were reported in more than half of all patients. The incidence of patients experiencing at least one adverse event (drug-related and non-drug-related) was higher in the infants and toddlers compared to children and adolescents. The most frequently occurring adverse events by MedDRA system organ class were General disorders and administration site conditions, Gastrointestinal disorders, and Skin and subcutaneous tissue disorders. There was no increase in drug-related adverse events associated with higher doses of moxifloxacin. No cardiovascular morbidity or mortality attributable to QT prolongation occurred. No musculoskeletal events were reported up to the 3-month follow-up visit.
Pharmacokinetics: Absorption and bioavailability: Following oral administration moxifloxacin is absorbed rapidly and almost completely. The absolute bioavailability amounts to approx. 91%.
Pharmacokinetics are linear in the range of 50 - 1200 mg single dose and up to 600 mg once daily dosing over 10 days. Steady state is reached within 3 days. Following a 400 mg oral dose peak concentrations of 3.1 mg/L are reached within 0.5 - 4 hours post application. Peak and trough plasma concentrations at steady state (400 mg once daily) were 3.2 and 0.6 mg/L, respectively.
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 fluoroquinolones, this effect is clinically not relevant. Therefore, Moxifloxacin (Avelox) can be administered independently from meals.
After a single 400 mg intravenous 1 hour infusion peak concentrations of approximately 4.1 mg/L were reached in the plasma at the end of infusion which corresponds to a mean increase of approx. 26 % relative to the oral application. Exposure to drug in terms of AUC at a value of approximately 39 mg*h/L is only slightly higher compared to the exposure after oral administration (35 mg*h/L) in accordance with the absolute bioavailability of approximately 91%.
Following multiple intravenous dosing (1hour infusion), peak and trough plasma concentrations at steady state (400 mg once daily) were between 4.1 to 5.9 and 0.43 to 0.84 mg/L respectively. At steady-state the exposure to drug within the dosing interval is approximately 30 % higher than after the first dose. In patients mean steady state concentrations of 4.4 mg/L were observed at the end of a 1-hour infusion.
Distribution: Moxifloxacin is distributed very rapidly to extra vascular spaces. Exposure to drug in terms of AUC (AUC_norm = 6 kg*h/L) is high with a volume of distribution at steady state (V_ss) of approximately 2 L/kg. In saliva peak concentrations higher than those of plasma may be reached. In in vitro and ex vivo experiments over a range of 0.02 to 2 mg/L a protein binding of approximately 45 % independent from the concentration of the drug was determined. Moxifloxacin is mainly bound to serum albumin. Due to this low value high free peak concentrations > 10x MIC are observed.
Moxifloxacin reaches high concentrations in tissues like lung (epithelial fluid, alveolar macrophages, biotic tissue), the sinuses (maxillary and ethmoid sinus, nasal polypi) and inflamed lesions (cantharide blister fluid) where total concentrations exceeding those of the plasma concentrations are reached. High free drug concentrations are measured in interstitial body water (saliva, intramuscular, subcutaneous). In addition, high drug concentrations were detected in abdominal tissues and fluids and female genital tract.
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 undergoes Phase II biotransformation and is excreted via renal and biliary/faecal pathways as unchanged drug as well as in form of a sulfo-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive. Neither in in vitro nor in clinical Phase I studies metabolic pharmacokinetic interactions with other drugs undergoing Phase I biotransformation involving Cytochrome P-450 enzymes were observed.
Independent from the route of administration the metabolites M1 and M2 are found in the plasma at concentrations lower than the parent drug. Preclinical investigations adequately covered both metabolites thus excluding potential implications with respect to safety and tolerability.
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. Renal clearance amounted to about 24 - 53 mL/min suggesting partial tubular reabsorption of the drug from the kidneys. Concomitant administration of ranitidine and probenecid did not alter renal clearance of the drug.
Mass balance of the mother compound and Phase II metabolites of moxifloxacin yielded an almost complete recovery of approximately 96-98% independent from the route of administration with no indication of oxidative metabolism.
Geriatric patients: Pharmacokinetics of moxifloxacin are not affected by age.
Gender: There was a 33% difference in the pharmacokinetics (AUC, C_max) of moxifloxacin between male and female subjects. Drug absorption was unaffected by gender. These differences in the AUC and C_max were attributable to the differences in body weight rather than gender. They are not considered as clinically relevant.
Ethnic differences: Possible interethnic differences were examined in Caucasian, Japanese, Black and other ethnic groups. No clinically relevant interethnic differences in pharmacokinetics could be detected.
Pediatric Patients: Pharmacokinetics of moxifloxacin were studied after single dose intravenous (i.v.) administration (1 h infusion) in pediatric patients ranging from 3 months to <14 years. The corresponding PK parameters are summarized in the subsequent table. (See Table 6.)

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These data were used to derive oral and i.v. dosing schemes for a clinical Phase III study in pediatric patients as previously mentioned in Pharmacodynamics. A population PK analysis of data from Phase III with i.v. and sequential i.v. to oral treatment confirmed that the dosing schemes lead to a systemic moxifloxacin exposure which is comparable to the exposure seen in adult subjects. This is in the effective range for antimicrobial treatment based on PK/PD considerations (AUC/MIC). For pediatric patients <12 years of age and <45 kg body weight a switch from once daily to a bid dosing is suitable to avoid overly high peak concentrations. The absolute bioavailability of moxifloxacin was estimated at 86%.
Patients with 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. hemodialysis and continuous ambulatory peritoneal dialysis.
Patients with 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 "Precautions" in patients with liver cirrhosis).
Toxicology: Preclinical safety data: In a local tolerability study performed in dogs, no signs of local intolerability were seen when moxifloxacin was administered intravenously. After intra-arterial injection inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.
Carcinogenicity, Mutagenicity: Although conventional long-term studies to determine the carcinogenic potential of moxifloxacin have not been performed, the drug has been subject to a range of in vitro and in vivo genotoxicity tests. In addition, an accelerated bioassay for human carcinogenesis (initiation/promotion assay) was performed in rats. Negative results were obtained in 4 strains of the Ames test, in the HPRT mutation assay in Chinese hamster ovary cells and in the UDS assay in rat primary hepatocytes. As with other fluoroquinolones the Ames test with TA 102 was positive and the in vitro test in the Chinese hamster v79 cells showed chromosomal abnormalities at high concentrations (300 mcg/mL). However, the in vivo micronucleus assay in the mouse was negative. An additional in vivo assay, the dominant lethal assay in the mouse, was negative as well. It is concluded that the negative in vivo results adequately reflect the in vivo situation in terms of genotoxicity. No evidence of carcinogenicity was found in an initiation/promotion assay in rats.
ECG: At high concentrations, moxifloxacin is an inhibitor of the delayed rectifier potassium current of the heart and may thus cause prolongations of the QT-interval. Toxicological studies performed in dogs using oral doses of ≥ 90 mg/kg leading to plasma concentrations ≥ 16 mg/L caused QT-prolongations, but no arrhythmias. Only after very high cumulative intravenous administration of more than 50 fold the human dose (> 300 mg/kg), leading to plasma concentrations of ≥ 200 mg/L (more than 30 fold the therapeutic level after intravenous administration), reversible, non-fatal ventricular arrhythmias were seen.
Arthrotoxicity: Fluoroquinolones are known to cause lesions in the cartilage of the major diarthrodial joints in immature animals. The lowest oral dose of moxifloxacin causing joint toxicity in juvenile dogs was four times maximum recommended therapeutic dose (400 mg/50 kg person) on a mg/kg basis, with plasma concentrations two to three times higher than those at the recommended therapeutic dose.
Reprotoxicity: Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in rats (per os and i.v.) and monkeys (per os) did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. Skeletal malformations were observed in rabbits that had been treated with an intravenous dose of 20 mg/kg. This study result is consistent with the known effects of fluoroquinolones on skeletal development (see "Use in Pregnancy & Lactation"). There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic concentrations. In rats, decreased foetal weights, an increased prenatal loss, a slightly increased duration of pregnancy and an increased spontaneous activity of some male and female offspring was observed at doses which were 63 times the maximum recommended dose on a mg/kg basis with plasma concentrations in the range of the human therapeutic dose.

Moxifloxacin (Avelox) 400 mg film-coated tablets are indicated for the treatment of the following bacterial infections caused by susceptible strains: Respiratory tract infections: Acute exacerbations of chronic bronchitis, Community acquired pneumonia (CAP) including CAP caused by multi-drug resistant strains*, Acute sinusitis.
Uncomplicated skin and skin structure infections.
Uncomplicated pelvic inflammatory disease (i.e. infections of female upper genital tract, including salpingitis and endometritis).
Complicated skin and skin structure infections (incl. diabetic foot infections).
Complicated intraabdominal infections including polymicrobial infections such as abscesses.

Method of administration: The film-coated tablet should be swallowed whole with sufficient liquid and may be taken independent of meals.
Dosage regimen: Dose (adults): The recommended dose for Moxifloxacin (Avelox) is 400 mg once daily (1 film-coated tablet) for the previously mentioned indications and should not be exceeded.
Duration of treatment: The duration of treatment should be determined by the severity of the indication or clinical response. The following general recommendations for the treatment of infections are made: See Table 7.

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The recommended duration of treatment for the indication being treated should not be exceeded.
Moxifloxacin (Avelox) 400 mg film-coated tablets has been studied in clinical trials for up to 21 days (in complicated skin and skin structure infections).
Missed Dose: If a dose is missed, it should be taken as soon as the patient remembers on the same day. Double doses should not be taken to compensate for a missed dose.
Additional information on special populations: Pediatric patients: The efficacy of Moxifloxacin (Avelox) in children and adolescents has not been established. Currently available data are described in Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions. No recommendation on posology can be made.
The safety of Moxifloxacin (Avelox) in children below the age of 6 years has not been established. Currently available data are described in Adverse Reactions, Pharmacology: Pharmacodynamics, Pharmacokinetics and Toxicology: Preclinical safety data under Actions.
Geriatric patients: No adjustment of dosage is required in elderly.
Ethnic differences: No adjustment of dosage is required in ethnic groups.
Patients with hepatic impairment: No dosage adjustment is required in patients with impaired liver function (see "Precautions" in patients with liver cirrhosis).
Patients with renal impairment: No dose adjustment is required in patients with renal impairment (including creatinine clearance ≤ 30 mL/min/1.73 m²) and in patients on chronic dialysis i.e. hemodialysis and continuous ambulatory peritoneal dialysis.

Only limited data on overdose are available. Single doses of up to 1200 mg and multiple doses of 600 mg moxifloxacin 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 including ECG measurements should be instituted as dictated by the patient's clinical status.
The use of charcoal early after oral administration may be useful to prevent excessive increase of systemic exposure to moxifloxacin in cases of overdosage.

Known hypersensitivity to moxifloxacin or other fluoroquinolones or any of the excipients.
Pregnancy and lactation.

Hypersensitivity: In some instances, the hypersensitivity and allergic reactions already occurred after the first administration and the doctor should be informed immediately.
Anaphylactic reactions in very rare instances can progress to a life threatening shock, in some instances after the first administration. In these cases the treatment with Moxifloxacin (Avelox) has to be discontinued, medical treatment (e.g. treatment for shock) is required.
Cases of bullous skin reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with Moxifloxacin (Avelox) (see "Adverse Reactions"). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.
Cardiac disorders: Moxifloxacin (Avelox) has been shown to prolong the QT interval of the electrocardiogram in some patients. 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. As the magnitude of QT prolongation may increase with increasing concentrations of the drug, the recommended dose and the infusion rate (400 mg within 60 minutes) should not be exceeded. However, in patients suffering from pneumonia no correlation between plasma concentrations of moxifloxacin and QTc prolongation was observed. QT prolongation may lead to an increased risk for ventricular arrhythmias including torsades de pointes. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with Moxifloxacin (Avelox) treatment in clinical studies with more than 9000 patients, however certain predisposing conditions may increase the risk for ventricular arrhythmias.
Therefore, treatment with Moxifloxacin (Avelox) should be avoided due to the lack of clinical experience with the drug in these patient populations: in patients with known prolongation of the QT interval; in patients with uncorrected hypokalemia; in patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents.
Moxifloxacin (Avelox) should be used with caution as an additive effect of moxifloxacin on the QT interval cannot be excluded for the following conditions: in patients treated concomitantly with drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics and tricyclic antidepressants; in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia, acute myocardial ischemia; in patients with liver cirrhosis as preexisting QT prolongation in these patients cannot be excluded; in women and elderly patients who, both, may be more susceptible to QTc-prolonging drugs.
Hepatobiliary system: Cases of fulminant hepatitis potentially leading to liver failure (including fatal cases) have been reported with Moxifloxacin (Avelox) (see "Adverse Reactions"). Patients should be advised to contact their doctor immediately prior to continuing treatment if symptoms related to liver failure occur.
Seizures: Seizures may occur with fluoroquinolone therapy. It 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), which may predispose to seizures or lower the seizure threshold.
Gastrointestinal system: Antibiotic associated colitis has been reported with the use of broad-spectrum antibiotics including Moxifloxacin (Avelox); therefore it is important to consider this diagnosis in patients who develop serious diarrhoea in association with the use of Moxifloxacin (Avelox). In this clinical situation adequate therapeutic measures should be initiated immediately. Drugs inhibiting peristalsis are contraindicated in patients who develop serious diarrhea.
Myasthenia gravis: Moxifloxacin (Avelox) should be used with caution in patients with myasthenia gravis because the symptoms can be exacerbated.
Tendinitis and tendon rupture: Tendinitis and tendon rupture (predominantly Achilles tendon), sometimes bilateral, may occur with fluoroquinolone therapy including moxifloxacin, even within the first 48 hours of treatment. 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 including renal failure and patients with solid organ transplants. At the first sign of tendinitis (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 the antibiotic treatment should be discontinued.
Complicated pelvic inflammatory disease: For patients with complicated pelvic inflammatory disease (e.g. associated with a tubo-ovarian or pelvic abscess), for whom an intravenous treatment is considered necessary, treatment with Moxifloxacin (Avelox) 400 mg film-coated tablets is not recommended.
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 "Pharmacology: Pharmacodynamics under Actions").
Interaction with tests: Moxifloxacin in vitro activity may interfere with the Mycobacterium spp. culture test by suppression of mycobacterial growth, causing false negative results in specimens from patients currently taking Moxifloxacin (Avelox).
Peripheral neuropathy: Cases of sensory or sensorimotor polyneuropathy resulting in paresthesias, hypoesthesias, dysesthesias, or weakness have been reported in patients receiving fluoroquinolones including Moxifloxacin (Avelox). Patients under treatment with Moxifloxacin (Avelox) 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 "Adverse Reactions").
Psychiatric reactions: Psychiatric reactions may occur even after the first administration of fluoroquinolones, including moxifloxacin. In very rare cases depression or psychotic reactions have progressed to suicidal thoughts and self-injurious behavior such as suicide attempts (see "Adverse Reactions"). In the event that the patient develops these reactions, Moxifloxacin (Avelox) should be discontinued and appropriate measures instituted. Caution is recommended if Moxifloxacin (Avelox) is to be used in psychotic patients or in patients with a history of psychiatric disease.
Genital tract infections: Because of the widespread and rising prevalence of fluoroquinolone-resistant Neisseria gonorrhoeae infections, monotherapy with moxifloxacin should be avoided in patients with pelvic inflammatory disease, unless fluoroquinolone-resistant N. gonorrhoeae can be excluded. If fluoroquinolone-resistant N. gonorrhoeae can not be excluded, the addition of an appropriate antibiotic which is regularly active against N. gonorrhoeae (e.g., a cephalosporin) to empirical moxifloxacin therapy, should be considered.
Dysglycemia: As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with Moxifloxacin (Avelox). In Moxifloxacin (Avelox)-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g. sulfonylurea) or with insulin. In diabetic patients, careful monitoring of blood glucose is recommended (see "Adverse Reactions").
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.
Information about excipients: 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.
Effects on ability to drive or use machines: 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 "Adverse Reactions").

Pregnancy: The safe use of Moxifloxacin (Avelox) in human pregnancy has not been established. Reversible joint injuries are described in children receiving some fluoroquinolones, however this effect has not been reported as occurring on exposed fetuses. Animal studies have shown reproductive toxicity. The potential risk for humans is unknown.
Consequently, the use of Moxifloxacin (Avelox) during pregnancy is contraindicated.
Lactation: As with other fluoroquinolones, Moxifloxacin (Avelox) has been shown to cause lesions in the cartilage of the weight bearing joints of immature animals. Preclinical evidence indicates that small amounts of moxifloxacin may be secreted in human milk. There is no data available in lactating or nursing women. Therefore, the use of Moxifloxacin (Avelox) in nursing mothers is contraindicated.

Tabulated list of adverse reactions: Adverse drug reactions (ADRs) based on all clinical studies with moxifloxacin 400 mg (oral and sequential [IV/oral]/intravenous only administration) sorted by CIOMS III categories of frequency (overall n = 17,951, including n = 4,583 from sequential/intravenous therapy studies; status: May 2010) are listed as follows: ADRs listed under "common" were observed with a frequency below 3% with the exception of nausea and diarrhea.
ADRs derived from post marketing reports (status: May 2010) are printed in bold italic.
Within each frequency grouping, undesirable effects 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). (See Table 8.)

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In isolated instances, some serious adverse drug reactions may be long-lasting (> 30 days) and disabling; such as tendinitis, 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: Ventricular tachyarrhythmias, Hypotension, Edema, Antibiotic associated colitis (in very rare cases associated with life threatening complications), Seizures of various clinical manifestations (incl. grand mal convulsions), Hallucinations, Renal impairment and Renal failure (due to dehydration esp. in elderly with pre-existing renal disorders).
Additional information on special populations: Pediatric patients: Adverse reactions in children (>3 months - <18 years) were derived from a clinical study in pediatric patients with complicated intra-abdominal infection. For the safety analysis, data from a total of 301 pediatric patients treated with moxifloxacin were available, thereof 15 patients below the age of 6 years and 286 patients at the age of 6 - <18 years.
Cartilage damage of weight-bearing joints in juvenile animals is a known class effect of fluoroquinolones. Therefore, musculoskeletal events were carefully monitored and followed up over 1 year after the study treatment. The musculoskeletal adverse events observed in the study were mostly rated as mild in intensity, and were equally distributed among the moxifloxacin and the comparator groups. There were no events indicating chondropathy.
Moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients (see Precautions). The ECG analyses in pediatric patients revealed that QT prolongation is common. No cardiovascular morbidity or mortality attributable to QTc prolongation occurred with moxifloxacin treatment in the pediatric study. For specific warnings and precautions for use referring to QT prolongation, see Special warnings and precautions for use.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. Sub-set analyses by age groups did not reveal any age-related exceptions. However, the low number of children below the age of 6 years limits the analysis of adverse reactions in younger children.

Antacids, minerals and multi-vitamins: Concomitant ingestion of Moxifloxacin (Avelox) together with antacids, minerals and multi-vitamins may result in impaired absorption of moxifloxacin after oral administration due to formation of chelate complexes with the multi-valent cations contained in these preparations. This may lead to plasma concentrations considerably lower than desired. Hence, antacids, anti-retroviral drugs (e.g. didanosine), and other preparations containing magnesium or aluminum, sucralfate and agents containing iron or zinc should be administered at least 4 hours before or 2 hours after ingestion of an oral moxifloxacin dose.
Warfarin: No interaction during concomitant treatment with warfarin on pharmacokinetics, prothrombin time and other coagulation parameters has been observed.
Changes in INR (International Normalized Ratio): Cases of increased anticoagulant activity have been reported in patients receiving anticoagulants concurrently with antibiotics, including Moxifloxacin (Avelox). The infectious disease (and its accompanying inflammatory process), age and general status of the patient are risk factors. Although an interaction between Moxifloxacin (Avelox) 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.
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.
Charcoal: Concomitant dosing of charcoal and 400 mg oral Moxifloxacin (Avelox) 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%).
Food and dairy products: Absorption of moxifloxacin was not altered by food intake (including dairy products). Moxifloxacin (Avelox) can be taken independent from food intake.

Incompatibilities: Not applicable.
Instructions for use/handling: Store in the original package in order to protect from moisture.

Store at temperatures not exceeding 25°C.

Quinolones

J01MA14 - moxifloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.

Rx