Moxifloxacin (Page 3 of 11)

5.7 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.

5.8 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)]

5.9 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.

5.10 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.

5.11 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)].

5.12 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)].

5.13 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)].

5.14 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.

6 ADVERSE REACTIONS

The following serious and otherwise important adverse reactions are discussed in greater detail in the warnings and precautions section of the label:

• Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects [see Warnings and Precautions (5.1)]

• 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)]

• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.5)]

• QT Prolongation [see Warnings and Precautions (5.6)]

• Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions (5.7)]

• Hypersensitivity Reactions [see Warnings and Precautions (5.8)]

• Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions (5.9)]

Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.10)]

• Blood Glucose Disturbances [see Warnings and Precautions (5.12)]

• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.13)]

• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.14)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to moxifloxacin in 14981 patients in 71 active controlled Phase II to IV clinical trials in different indications [see Indications and Usage (1)]. The population studied had a mean age of 50 years (approximately 73% of the population was less than 65 years of age), 50% were male, 63% were Caucasian, 12% were Asian and 9% were Black. Patients received moxifloxacin 400 mg once daily oral, intravenous, or sequentially (intravenous followed by oral). Treatment duration was usually 6 to 10 days, and the mean number of days on therapy was 9 days.

Discontinuation of moxifloxacin due to adverse reactions occurred in 5% of patients overall, 4% of patients treated with 400 mg PO, 4% with 400 mg intravenous and 8% with sequential therapy 400 mg oral/intravenous. The most common adverse reactions (>0.3%) leading to discontinuation with the 400 mg oral doses were nausea, diarrhea, dizziness, and vomiting. The most common adverse reaction leading to discontinuation with the 400 mg intravenous dose was rash. The most common adverse reactions leading to discontinuation with the 400 mg intravenous/oral sequential dose were diarrhea, pyrexia.

Adverse reactions occurring in 1% of moxifloxacin-treated patients and less common adverse reactions, occurring in 0.1 to 1% of moxifloxacin-treated patients, are shown in Tables 2 and Table 3 , respectively. The most common adverse drug reactions (3%) are nausea, diarrhea, headache, and dizziness.

Table 2 Common (1% or more) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin

System Organ Class Adverse Reactions % (N=14,981)
Blood and Lymphatic System Disorders Anemia 1
Gastrointestinal Disorders Nausea 7
Diarrhea 6
Vomiting 2
Constipation 2
Abdominal pain 2
Dyspepsia 1
General Disorders and Administration Site Conditions Pyrexia 1
Investigations Alanine aminotransferase increased 1
Metabolism and Nutritional Disorder Hypokalemia 1
Nervous System Disorders HeadacheDizziness 43
Psychiatric Disorders Insomnia 2

Table 3 Less Common (0.1 to less than 1%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Moxifloxacin (N=14,981)

*
System Organ Class Adverse Reactions
Blood and Lymphatic System Disorders Thrombocythemia Eosinophilia Neutropenia Thrombocytopenia Leukopenia Leukocytosis
Cardiac Disorders Atrial fibrillation Palpitations Tachycardia Angina pectoris Cardiac failureCardiac arrest Bradycardia
Ear and Labyrinth Disorders Vertigo Tinnitus
Eye Disorders Vision blurred
Gastrointestinal Disorders Dry mouth Abdominal discomfort Flatulence Abdominal distention Gastritis Gastroesophageal reflux disease
General Disorders and Administration Site Conditions Fatigue Chest pain Asthenia Pain Malaise Infusion site extravasation EdemaChills Chest discomfort Facial pain
Hepatobiliary disorders Hepatic function abnormal
Infections and Infestations Candidiasis Vaginal infection Fungal infection Gastroenteritis
Investigations Aspartate aminotransferase increased Gamma-glutamyltransferase increased Blood alkaline phosphatase increased Electrocardiogram QT prolonged Blood lactate dehydrogenase increased Blood amylase increased Lipase increased Blood creatinine increased Blood urea increased Hematocrit decreased Prothrombin time prolonged Eosinophil count increased Activated partial thromboplastin time prolonged Blood triglycerides increased Blood uric acid increased
Metabolism and Nutrition Disorders Hyperglycemia Anorexia HHyperlipidemia Decreased appetite Dehydration
Musculoskeletal and Connective Tissue Disorders Back pain Pain in extremity Arthralgia Muscle spasms Musculoskeletal pain
Nervous System Disorders Dysgeusia Somnolence Tremor Lethargy Paresthesia Hypoesthesia Syncope
Psychiatric Disorders Anxiety Confusional state Agitation Depression Nervousness Restlessness Hallucination Disorientation
Renal and Urinary Disorders Renal failure Dysuria
Reproductive System and Breast Disorders Vulvovaginal pruritus
Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Asthma Wheezing Bronchospasm
Skin and Subcutaneous Tissue Disorders Rash Pruritus Hyperhidrosis Erythema Urticaria Dermatitis allergic Night sweats
Vascular Disorders Hypertension HypotensionPhlebitis *

Laboratory Changes

Changes in laboratory parameters, which are not listed above and which occurred in 2% or more of patients and at an incidence greater than in controls included: increases in mean corpuscular hemoglobin (MCH), neutrophils, white blood cells (WBCs), prothrombin time (PT) ratio, ionized calcium, chloride, albumin, globulin, bilirubin; decreases in hemoglobin, red blood cells (RBCs), neutrophils, eosinophils, basophils, glucose, oxygen partial pressure (pO2 ), bilirubin, and amylase. It cannot be determined if any of the above laboratory abnormalities were caused by the drug or the underlying condition being treated.

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