Avelox

Generic Name: moxifloxacin hydrochloride

Dosage Form: tablet, film coated - injection, solution
FULL PRESCRIBING INFORMATION

WARNING:

Fluoroquinolones, including Avelox®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk 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 [see Warnings and Precautions (5.1)].

 Fluoroquinolones, including Avelox, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Avelox in patients with known history of myasthenia gravis [see Warnings and Precautions (5.2)].

Indications and Usage for Avelox

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Avelox and other antibacterial drugs, Avelox should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Avelox  Tablets and IV are indicated for the treatment of adults (≥ 18 years of age) with infections caused by susceptible strains of the designated microorganisms in the conditions listed below [see Dosage and Administration (2) and Use In Specific Populations (8.5)].

Culture and Susceptibility Testing

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to moxifloxacin [see Clinical Pharmacology (12.4)]. Therapy with Avelox may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.

Acute Bacterial Sinusitis

Avelox is indicated for the treatment of Acute Bacterial Sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)].

Acute Bacterial Exacerbation of Chronic Bronchitis

Avelox is indicated for the treatment of Acute Bacterial Exacerbation of Chronic Bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, methicillin-susceptible Staphylococcus aureus, or Moraxella catarrhalis [see Clinical Studies (14.1)].

Community Acquired Pneumonia

Avelox is indicated for the treatment of Community Acquired Pneumonia caused by Streptococcus pneumoniae (including multi-drug resistant strains*), Haemophilus influenzae, Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus, Klebsiella pneumoniae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae.

* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (minimum inhibitory concentrations [MIC] ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole [see Clinical Studies (14.2)].

Uncomplicated Skin and Skin Structure Infections

Avelox is indicated for the treatment of Uncomplicated Skin and Skin Structure Infections caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes [see Clinical Studies (14.5)].

Complicated Skin and Skin Structure Infections

Avelox is indicated for the treatment of Complicated Skin and Skin Structure Infections caused by methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae [see Clinical Studies (14.6)].

Complicated Intra-Abdominal Infections

Avelox is indicated for the treatment of Complicated Intra-Abdominal Infections including polymicrobial infections such as abscess caused by Escherichia coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, Enterococcus faecalis, Proteus mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, or Peptostreptococcus species [see Clinical Studies (14.7)].

Avelox Dosage and Administration

Dosage in Adult Patients

The dose of Avelox is 400 mg (orally or as an intravenous infusion) once every 24 hours. The duration of therapy depends on the type of infection as described in Table 1.

Table 1: Dosage and Duration of Therapy in Adult Patients

* Due to the designated pathogens [see Indications and Usage (1), for IV use, see Use in Specific Populations (8.5)]. † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician
Type of Infection*	Dose Every 24 hours	Duration†  (days)
Acute Bacterial Sinusitis (1.1)	400 mg	10
Acute Bacterial Exacerbation of Chronic Bronchitis (1.2)	400 mg	5
Community Acquired Pneumonia	400 mg	7-14
Uncomplicated Skin and Skin Structure Infections (SSSI ) (1.4)	400 mg	7
Complicated SSSI (1.5)	400 mg	7-21
Complicated Intra-Abdominal Infections (1.6)	400 mg	5-14

 Intravenous formulation is indicated when it offers a route of administration advantageous to the patient (for example, patient cannot tolerate an oral dosage form). When switching from intravenous to oral formulation, no dosage adjustment is necessary. Patients whose therapy is started with Avelox IV may be switched to Avelox Tablets when clinically indicated at the discretion of the physician.

Drug Interactions with Multivalent Cations

Oral doses of Avelox should be administered at least 4 hours before or 8 hours after products containing magnesium, aluminum, iron or zinc, including antacids, sucralfate, multivitamins and VIDEX® (didanosine) chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Administration Instructions

Avelox Tablets

Avelox Tablets can be taken with or without food, drink fluids liberally.

Avelox IV

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Avelox IV should be administered by INTRAVENOUS infusion only. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

Avelox IV should be administered by intravenous infusion over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in place. Caution: rapid or bolus intravenous infusion must be avoided.

Because only limited data are available on the compatibility of Avelox intravenous injection with other intravenous substances, additives or other medications should not be added to Avelox IV or infused simultaneously through the same intravenous line. If the same intravenous line or a Y-type line is used for sequential infusion of other drugs, or if the “piggyback” method of administration is used, the line should be flushed before and after infusion of Avelox IV with an infusion solution compatible with Avelox IV as well as with other drug(s) administered via this common line.

Avelox IV is compatible with the following intravenous solutions at ratios from 1:10 to 10:1
0.9% Sodium Chloride Injection, USP	Sterile Water for Injection, USP
1M Sodium Chloride Injection	10% Dextrose for Injection, USP
5% Dextrose Injection, USP	Lactated Ringer’s for Injection

Preparation for Administration of Avelox IV

To prepare Avelox IV injection premix in flexible containers:

1. Close flow control clamp of administration set.


2. Remove cover from port at bottom of container.


3. Insert piercing pin from an appropriate transfer set (for example, one that does not require excessive force, such as ISO compatible administration set) into port with a gentle twisting motion until pin is firmly seated.

NOTE: Refer to complete directions that have been provided with the administration set.

Dosage Forms and Strengths

Avelox Tablets

• Containing moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin)


• Oblong, dull red film-coated tablets


• Imprinted with BAYER on one side and M400 on the other

Avelox IV

• Containing 400 mg moxifloxacin in 0.8% saline (moxifloxacin hydrochloride in sodium chloride injection) with pH ranging from 4.1 to 4.6.


• Ready-to-use 250 mL latex-free flexibags. No further dilution is necessary


• Sterile, preservative free, 0.8% sodium chloride aqueous solution of moxifloxacin hydrochloride

Contraindications

Avelox is contraindicated in persons with a history of hypersensitivity to moxifloxacin or any member of the quinolone class of antimicrobial agents.

Warnings and 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. [see Adverse Reactions (6.4) and Patient Counseling Information (17.3).]

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including Avelox, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, 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 [see Patient Counseling Information (17.3)].

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).

The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia and patients receiving Class IA (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic agents, due to the lack of clinical experience with the drug in these patient populations.

Pharmacokinetic studies between Avelox and other drugs that prolong the QT interval such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants have not been performed. An additive effect of Avelox and these drugs cannot be excluded; therefore caution should be exercised when Avelox is given concurrently with these drugs. In premarketing clinical trials, the rate of cardiovascular adverse events was similar in 798 Avelox and 702 comparator treated patients who received concomitant therapy with drugs known to prolong the QTc interval.

Avelox should be used with caution in patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia, acute myocardial ischemia. 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. QT prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. 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. Elderly patients using IV Avelox may be more susceptible to drug-associated QT prolongation [see Use In Specific Populations (8.5)]. In addition, Avelox should be used with caution in patients with mild, moderate, or severe liver cirrhosis [see Clinical Pharmacology (12.3) and Patient Counseling Information (17.3)].

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. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Avelox should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Oxygen, intravenous steroids, and airway management, including intubation, may be administered as indicated [see Adverse Reactions (6) and Patient Counseling Information (17.3)].

Other Serious and Sometimes Fatal Reactions

Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Avelox . These events 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

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Patient Counseling Information (17.3) and Adverse Reactions (6.4).

Central Nervous System Effects

 Fluoroquinolones, including Avelox, may cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia [see Adverse Reactions (6.2, 6.4)].

 Convulsions and increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones. Fluoroquinolones may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These 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, Avelox should be used 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 [see Drug Interactions (7.4) Adverse Reactions (6.2, 6.4) and Patient Counseling Information (17.3)].

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 require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic 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 [see Adverse Reactions (6.2) and Patient Counseling Information (17.3)].

Peripheral Neuropathy

Rare 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 quinolones [see Adverse Reactions (6.2) and Patient Counseling Information (17.3)].

Arthropathic Effects in Animals

The oral administration of Avelox caused lameness in immature dogs. 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 Animal Toxicology and/or Pharmacology (13.2)].

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 quinolone antibiotics after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs [see Adverse Reactions (6.4) and Pharmacokinetics (12.3)].

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 [see Patient Counseling Information (17.1)].

Adverse Reactions

Serious and Otherwise Important Adverse Reactions

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

• Tendinopathy and Tendon Rupture [see Warnings and Precautions (5.1)]


• QT Prolongation [see Warnings and Precautions (5.3)]


• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]


• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.5)]


• Central Nervous System Effects [see Warnings and Precautions (5.6)]


• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]


• Peripheral Neuropathy [see Warnings and Precautions (5.8)]


• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.10)]


• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.11)]

Clinical Trial 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 Avelox in 14981 patients in 71 active controlled Phase II- 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 <65 years of age), 50% were male, 63% were Caucasian, 12% were Asian and 9% were Black. Patients received Avelox 400 mg once daily PO, IV, or sequentially (IV followed by PO). Treatment duration was usually 6-10 days, and the mean number of days on therapy was 9 days.

Discontinuation of Avelox due to adverse events occurred in 5.0% of patients overall, 4.1% of patients treated with 400 mg PO, 3.9% with 400 mg IV and 8.2% with sequential therapy 400 mg PO/IV. The most common adverse events leading to discontinuation with the 400 mg PO doses were nausea (0.8%), diarrhea (0.5%), dizziness (0.5%), and vomiting (0.4%). The most common adverse event leading to discontinuation with the 400 mg IV dose was rash (0.5%). The most common adverse events leading to discontinuation with the 400 mg IV/PO sequential dose were diarrhea (0.5%), pyrexia (0.4%).

Adverse reactions occurring in ≥1% of Avelox-treated patients and less common adverse reactions, occurring in 0.1 to <1% of Avelox-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 (≥ 1.0%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Avelox

* MedDRA Version 12.0
System Organ Class	Adverse Reactions*	% (N=14,981)
Blood and Lymphatic System Disorders	Anemia	1.1
Gastrointestinal Disorders	Nausea	6.9
	Diarrhea	6.0
	Vomiting	2.4
	Constipation	1.9
	Abdominal pain	1.5
	Abdominal pain upper	1.1
	Dyspepsia	1.0
General Disorders and Administration Site Conditions	Pyrexia	1.1
Investigations	Alanine aminotransferase increased	1.1
Metabolism and Nutritional Disorder	Hypokalemia	1
Nervous System Disorders	Headache	4.2
	Dizziness	3.0
Psychiatric Disorders	Insomnia	1.9

 

Table 3: Less Common (0.1 to <1.0%) Adverse Reactions Reported in Active-Controlled Clinical Trials with Avelox (N=14,981)

* MedDRA Version 12.0
System Organ Class	Adverse Reactions*
Blood and Lymphatic System Disorders	Thrombocythemia
	Eosinophilia
	Neutropenia
	Thrombocytopenia
	Leukopenia
	Leukocytosis
Cardiac Disorders	Atrial fibrillation
	Palpitations
	Tachycardia
	Cardiac failure congestive
	Angina pectoris
	Cardiac failure
	Cardiac 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
	Edema peripheral
	Pain
	Malaise
	Infusion site extravasation
	Edema
	Chills
	Chest discomfort
	Facial pain
Hepatobiliary disorders	Hepatic function abnormal
Infections and Infestations	Vulvovaginal candidiasis
	Oral candidiasis
	Vulvovaginal mycotic infection
	Candidiasis
	Vaginal infection
	Oral fungal infection
	Fungal infection
	Gastroenteritis
Investigations	Aspartate aminotransferase increased
	Gamma-glutamyltransferase increased
	Blood alkaline phosphatase increased
	Hepatic enzyme increased
	Electrocardiogram QT prolonged
	Blood lactate dehydrogenase increased
	Platelet count increased
	Blood amylase increased
	Blood glucose increased
	Lipase increased
	Hemoglobin decreased
	Blood creatinine increased
	Transaminases increased
	White blood cell count increased
	Blood urea increased
	Liver function test abnormal
	Hematocrit decreased
	Prothrombin time prolonged
	Eosinophil count increased
	Activated partial thromboplastin time prolonged
	Blood bilirubin increased
	Blood triglycerides increased
	Blood uric acid increased
	Blood pressure increased
Metabolism and Nutrition Disorders	Hyperglycemia
	Anorexia
	Hypoglycemia
	Hyperlipidemia
	Decreased appetite
	Dehydration
Musculoskeletal and Connective Tissue Disorders	Back pain
	Pain in extremity
	Arthralgia
	Myalgia
	Muscle spasms
	Musculoskeletal chest pain
	Musculoskeletal pain
Nervous System Disorders	Dysgeusia
	Somnolence
	Tremor
	Lethargy
	Paresthesia
	Tension headache
	Hypoesthesia
	Syncope
Psychiatric Disorders	Anxiety
	Confusional state
	Agitation
	Depression
	Nervousness
	Restlessness
	Hallucination
	Disorientation
Renal and Urinary Disorders	Renal failure
	Dysuria
	Renal failure acute
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