Moxifloxacin

SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAI NERVOUS SYTEM EFFECTS and EXACERBATION OF MYASTHENIA GRAVIS • Fluoroquinolones, including moxifloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions ( 5.1 )] , including: • Tendinitis and tendon rupture [see Warnings and Precautions ( 5.2 )] • Peripheral neuropathy [see Warnings and Precautions ( 5.3 )] • Central nervous system effects [see Warnings and Precautions ( 5.4 )] Discontinue moxifloxacin, immediately and avoid the use of fluoroquinolones, including moxifloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions ( 5.1 )] . • Fluoroquinolones, including moxifloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid moxifloxacin, in patients with known history of myasthenia gravis [see Warnings and Precautions ( 5.5 )]. • Because fluoroquinolones, including moxifloxacin, have been associated with serious adverse reactions [see Warnings and Precautions ( 5.1 - 5.13 )] , reserve moxifloxacin, for use in patients who have no alternative treatment options for the following indications: • Acute bacterial sinusitis [see Indications and Usage ( 1.6 )] • Acute bacterial exacerbation of chronic bronchitis [see Indications and Usage ( 1.7 )] WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRIAL NERVOUS SYSTEM EFFECTS and EXACERBATION OF MYASTHENIA GRAVIS See full prescribing information for complete boxed warning • Fluoroquinolones, including moxifloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together (5.1) including: • Tendinitis and tendon rupture (5.2) • Peripheral Neuropathy (5.3) • Central nervous system effects (5.4) Discontinue moxifloxacin immediately and avoid the use of fluoroquinolones, including moxifloxacin, in patients who experience any of these serious adverse reactions ( 5.1) • Fluoroquinolones, including moxifloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid moxifloxacin in patients with known history of myasthenia gravis (5.5) . • Because fluoroquinolones, including moxifloxacin, have been associated with serious adverse reactions ( 5.1 – 5.14 ), reserve moxifloxacin for use in patients who have no alternative treatment op

Prolongation of the QT interval and isolated cases of torsade de pointes has been reported. Avoid use in patients with known prolongation, proarrhythmic conditions such as clinically significant bradycardia or acute myocardial ischemia, hypokalemia, hypomagnesemia, and with drugs that prolong the QT interval. ( 5.6 , 7.5 , 8.5 ) · Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions, including anaphylactic reactions, may occur after first or subsequent doses of moxifloxacin. Discontinue moxifloxacin at first sign of skin rash, jaundice or any other sign of hypersensitivity. ( 5.7 , 5.8 ) · Clostridioides difficile -Associated Diarrhea: Evaluate if diarrhea occurs. ( 5.10 )

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including moxifloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting moxifloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see W arnings and Precautions ( 5.2 , 5.3 , 5.4 ) ]. Discontinue moxifloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including moxifloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinitis and Tendon Rupture Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.2 ) ]. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur within hours or days of starting moxifloxacin or as long as several months after completion of therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors 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. Discontinue moxifloxacin immediately 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. Avoid fluoroquinolones, including moxifloxacin, in patients who have a history of tendon disorders or who have experienced tendinitis or tendon rupture [see Adverse Reactions ( 6.2 ) ].

Peripheral Neuropathy Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of 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 moxifloxacin. Symptoms may occur soon after initiation of moxifloxacin and may be irreversible in some patients [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.1 , 6.2 ) ]. Discontinue moxifloxacin 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. Avoid fluoroquinolones, including moxifloxacin, in patients who have previously experienced peripheral neuropathy

Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, hallucinations, or paranoia; depression or suicidal thoughts or acts; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving moxifloxacin, discontinue moxifloxacin immediately and institute appropriate measures [see Adverse Reactions ( 6.1 , 6.2 )]. Central Nervous System Adverse Reactions Fluoroquinolones, including moxifloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), dizziness, and tremors. As with all fluoroquinolones, use moxifloxacin with caution 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. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving moxifloxacin, discontinue moxifloxacin immediately and institute appropriate measures [see Drug Interactions (7.4) Adverse Reactions ( 6.1 , 6.2 ), and Patient Counseling Information ( 17 )].

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

QT Prolongation Moxifloxacin has been shown to prolong the QT interval of the electrocardiogram in some patients. Following oral dosing with 400 mg of moxifloxacin 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 moxifloxacin 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 moxifloxacin may be more susceptible to drug-associated QT prolongation [see Use In Specific Populations ( 8.5 ) ]. 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 moxifloxacin [see Clinical Pharmacology ( 12.3 ) ]. 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 moxifloxacin 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 moxifloxacin 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 moxifloxacin tablet treated patients in a postmarketing observational study in which ECGs were not performed.

Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with fluoroquinolones, including moxifloxacin. These reactions may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: • Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome) • Vasculitis; arthralgia; myalgia; serum sickness • Allergic pneumonitis • Interstitial nephritis; acute renal insufficiency or failure • Hepatitis; jaundice; acute hepatic necrosis or failure • Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities Discontinue moxifloxacin immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures.

Hypersensitivity Reactions Serious anaphylactic reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including moxifloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Discontinue moxifloxacin at the first appearance of a skin rash or any other sign of hypersensitivity [see Warnings and Precautions ( 5.7 ) ]

Risk of Aortic Aneurysm and Dissection Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve moxifloxacin for use only when there are no alternative antibacterial treatments available.

Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including moxifloxacin, 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 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.

Arthropathic Effects in Animals In immature dogs, oral administration of moxifloxacin 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 ( 13.2 ) ].

Blood Glucose Disturbances As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with moxifloxacin. In moxifloxacin-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, sulfonylurea) or with insulin. Severe cases of hypoglycemia resulting in coma or death have been reported. In diabetic patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs, discontinue moxifloxacin and initiate appropriate therapy immediately [see Adverse Reactions ( 6.1 ), Drug Interactions ( 7.3 ) and Patient Counseling Information ( 17 )].

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 moxifloxacin, after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Moxifloxacin therapy should be discontinued if phototoxicity occurs [see Clinical Pharmacology ( 12.2 ) ].

Development of Drug Resistant Bacteria Prescribing moxifloxacin 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.