September 3, 2015
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Avelox

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Avelox




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Tendinopathy And Tendon Rupture

Fluoroquinolones, including AVELOX, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. AVELOX should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Exacerbation Of Myasthenia Gravis

Fluoroquinolones, including AVELOX, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid AVELOX in patients with known history of myasthenia gravis.

QT Prolongation

AVELOX has been shown to prolong the QT interval of the electrocardiogram in some patients. Following oral dosing with 400 mg of AVELOX the mean (± SD) change in QTc from the pre-dose value at the time of maximum drug concentration was 6 msec (± 26) (n = 787). Following a course of daily intravenous dosing (400 mg; 1 hour infusion each day) the mean change in QTc from the Day 1 pre-dose value was 10 msec (±22) on Day 1 (n=667) and 7 msec (± 24) on Day 3 (n = 667).

Avoid AVELOX in patients with the following risk factors due to the lack of clinical experience with the drug in these patient populations:

  • Known prolongation of the QT interval
  • Ventricular arrhythmias including torsade de pointes because QT prolongation may lead to an increased risk for these conditions
  • Ongoing proarrhythmic conditions, such as clinically significant bradycardia and acute myocardial ischemia,
  • Uncorrected hypokalemia or hypomagnesemia
  • Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents
  • Other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants

Elderly patients using intravenous AVELOX may be more susceptible to drug-associated QT prolongation. [see Use In Specific Populations]

In patients with mild, moderate, or severe liver cirrhosis, metabolic disturbances associated with hepatic insufficiency may lead to QT prolongation. Monitor ECG in patients with liver cirrhosis treated with AVELOX. [See CLINICAL PHARMACOLOGY]

The magnitude of QT prolongation may increase with increasing concentrations of the drug or increasing rates of infusion of the intravenous formulation. Therefore the recommended dose or infusion rate should not be exceeded.

In premarketing clinical trials, the rate of cardiovascular adverse reactions was similar in 798 AVELOX and 702 comparator treated patients who received concomitant therapy with drugs known to prolong the QTc interval. No excess in cardiovascular morbidity or mortality attributable to QTc prolongation occurred with AVELOX treatment in over 15,500 patients in controlled clinical studies, including 759 patients who were hypokalemic at the start of treatment, and there was no increase in mortality in over 18,000 AVELOX tablet treated patients in a postmarketing observational study in which ECGs were not performed.

Hypersensitivity Reactions

Serious anaphylactic reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including AVELOX. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Discontinue AVELOX at the first appearance of a skin rash or any other sign of hypersensitivity. [See Other Serious and Sometimes Fatal Reactions below]

Other Serious And Sometimes Fatal Reactions

Other serious and sometimes fatal reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with fluoroquinolones, including AVELOX. These reactions may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

Discontinue AVELOX immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures.

Central Nervous System Effects

Fluoroquinolones, including AVELOX, may cause central nervous system (CNS) reactions, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.

Convulsions and increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones, including AVELOX. AVELOX may also cause central nervous system (CNS) reactions including: dizziness, confusion, tremors, hallucinations, depression, and, suicidal thoughts or acts. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving AVELOX, the drug should be discontinued and appropriate measures instituted. As with all fluoroquinolones, use AVELOX when the benefits of treatment exceed the risks in patients with known or suspected CNS disorders (for example, severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold. [See DRUG INTERACTIONS]

Clostridium Difficile-Associated Diarrhea

Clostridium Difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AVELOX, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may 6 require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Peripheral Neuropathy

Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones including AVELOX. Symptoms may occur soon after initiation of AVELOX and may be irreversible. AVELOX should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation.

Arthropathic Effects in Animals

In immature dogs, oral administration of AVELOX caused lameness. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. [See Nonclinical Toxicology]

Blood Glucose Disturbances

As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with AVELOX. In AVELOX-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, sulfonylurea) or with insulin. In diabetic patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs, AVELOX should be discontinued and appropriate therapy should be initiated immediately. [See DRUG INTERACTIONS]

Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones, including AVELOX, after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. AVELOX should be discontinued if phototoxicity occurs. [See CLINICAL PHARMACOLOGY]

Development Of Drug Resistant Bacteria

Prescribing AVELOX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Antibacterial Resistance

Inform patients that antibacterial drugs including AVELOX should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When AVELOX is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AVELOX or other antibacterial drugs in the future.

Administration With Food, Fluids, and Drug Products Containing Multivalent Cations

Inform patients that AVELOX tablets may be taken with or without food. Advise patients drink fluids liberally.

Inform patients that AVELOX tablets should be taken at least 4 hours before or 8 hours after multivitamins (containing iron or zinc), antacids (containing magnesium or aluminum), sucralfate, or didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.

Serious and Potentially Serious Adverse Reactions

Inform patients about the following serious adverse reactions associated with AVELOX or other fluoroquinolones:

  • Tendon Disorders: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue AVELOX treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
  • Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis, as fluoroquinolones like AVELOX may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Advise patients to seek medical care right away if they have any worsening muscle weakness or breathing problems.
  • Prolongation of the QT interval: AVELOX may produce changes in the electrocardiogram (QTc interval prolongation). AVELOX should be avoided in patients receiving Class IA (for example quinidine, procainamide) or Class III (for example amiodarone, sotalol) antiarrhythmic agents. AVELOX may add to the QTc prolonging effects of other drugs such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants. Instruct patients to inform their physician of any personal or family history of QTc prolongation or proarrhythmic conditions such as recent hypokalemia, significant bradycardia, and acute myocardial ischemia. Advise patients to contact their physician if they experience palpitations or fainting spells while taking AVELOX.
  • Hypersensitivity Reactions: Advise patients that AVELOX may be associated with hypersensitivity reactions, including anaphylactic reactions, even following a single dose and to discontinue AVELOX at the first sign of a skin rash or other signs of an allergic reaction.
  • Convulsions: Inform the patients that convulsions have been reported in patients receiving fluoroquinolones, including AVELOX. Patients should notify their physician before taking AVELOX if they have a history of this condition and if they are taking NSAIDs.
  • Neurologic Adverse Effects (for example, dizziness, lightheadedness): Inform patients that AVELOX may cause dizziness, lightheadedness and vision disorders therefore, they should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.
  • Psychotic Reaction: Psychotic reactions sometimes resulting in self-injurious behavior have been reported in patients receiving fluoroquinolones. Patients should notify their physician if they have a history of psychiatric illness before taking AVELOX.
  • Peripheral Neuropathies: Inform patients that peripheral neuropathy has been associated with AVELOX use. Symptoms may occur soon after initiation of therapy and may be irreversible. Advise patients to discontinue AVELOX and seek medical care if symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop.
  • Blood Glucose Disturbances: Inform the patients that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue AVELOX and consult a physician.
  • Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones, including AVELOX. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking AVELOX. If patients need to be outdoors while using AVELOX, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician.
  • Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Plague Studies

Inform patients given AVELOX for plague that efficacy studies could not be conducted in humans for feasibility reasons. Therefore, approval for plague was based on efficacy studies conducted in animals.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed.

Moxifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in the Ames Salmonella reversion assay. As with other fluoroquinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.

Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 12 times the maximum recommended human dose based on body surface area) or at intravenous doses as high as 45 mg/kg/day, approximately equal to the maximum recommended human dose based on body surface area). At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C. Because no adequate or well-controlled studies have been conducted in pregnant women, AVELOX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis at oral doses as high as 500 mg/kg/day or 0.24 times the maximum recommended human dose based on systemic exposure (AUC), but decreased fetal body weights and slightly delayed fetal skeletal development (indicative of fetotoxicity) were observed. Intravenous administration of 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) to pregnant rats resulted in maternal toxicity and a marginal effect on fetal and placental weights and the appearance of the placenta. There was no evidence of teratogenicity at intravenous doses as high as 80 mg/kg/day. Intravenous administration of 20 mg/kg/day (approximately equal to the maximum recommended human oral dose based upon systemic exposure) to pregnant rabbits during organogenesis resulted in decreased fetal body weights and delayed fetal skeletal ossification. When rib and vertebral malformations were combined, there was an increased fetal and litter incidence of these effects. Signs of maternal toxicity in rabbits at this dose included mortality, abortions, marked reduction of food consumption, decreased water intake, body weight loss and hypoactivity. There was no evidence of teratogenicity when pregnant cynomolgus monkeys were given oral doses as high as 100 mg/kg/day (2.5 times the maximum recommended human dose based upon systemic exposure). An increased incidence of smaller fetuses was observed at 100 mg/kg/day. In an oral pre-and postnatal development study conducted in rats, effects observed at 500 mg/kg/day included slight increases in duration of pregnancy and prenatal loss, reduced pup birth weight and decreased neonatal survival. Treatment-related maternal mortality occurred during gestation at 500 mg/kg/day in this study.

Nursing Mothers

Moxifloxacin is excreted in the breast milk of rats. Moxifloxacin may also be excreted in human milk. Because of the potential for serious adverse reactions in infants who are nursing from mothers taking AVELOX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients and adolescents less than 18 years of age have not been established. AVELOX causes arthropathy in juvenile animals [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as AVELOX. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing AVELOX to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue AVELOX and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur. [See BOXED WARNING, and WARNINGS AND PRECAUTIONS]

In controlled multiple-dose clinical trials, 23% of patients receiving oral AVELOX were greater than or equal to 65 years of age and 9% were greater than or equal to 75 years of age. The clinical trial data demonstrate that there is no difference in the safety and efficacy of oral AVELOX in patients aged 65 or older compared to younger adults.

In trials of intravenous use, 42% of AVELOX patients were greater than or equal to 65 years of age, and 23% were greater than or equal to 75 years of age. The clinical trial data demonstrate that the safety of intravenous AVELOX in patients aged 65 or older was similar to that of comparator-treated patients. In general, elderly patients may be more susceptible to drug-associated effects of the QT interval. Therefore, AVELOX should be avoided in patients taking drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). [See WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY]

Renal Impairment

The pharmacokinetic parameters of moxifloxacin are not significantly altered in mild, moderate, severe, or end-stage renal disease. No dosage adjustment is necessary in patients with renal impairment, including those patients requiring hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) [see DOSAGE AND ADMINISTRATION, and CLINICAL PHARMACOLOGY].

Hepatic Impairment

No dosage adjustment is recommended for mild, moderate, or severe hepatic insufficiency (Child-Pugh Classes A, B, or C). However, due to metabolic disturbances associated with hepatic insufficiency, which may lead to QT prolongation, AVELOX should be used with caution in these patients [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 9/2/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
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