Moxifloxacin Tablets

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine (moxifloxacin tablets) affects you.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Tell your doctor if you have signs of high or low blood sugar like breath that smells like fruit, dizziness, fast breathing, fast heartbeat, feeling confused, feeling sleepy, feeling weak, flushing, headache, more thirsty or hungry, passing urine more often, shaking, or sweating.
• If you are taking warfarin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
• Do not use longer than you have been told. A second infection may happen.
• You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• Very bad and sometimes deadly allergic side effects have rarely happened. Talk with your doctor.
• Rarely, very bad and sometimes deadly effects have happened with this medicine (moxifloxacin tablets). These include muscle or joint, kidney, liver, blood, and other problems. Talk with the doctor if you have questions.
• A type of abnormal heartbeat (prolonged QT interval) can happen with this medicine. Call your doctor right away if you have a fast heartbeat, a heartbeat that does not feel normal, or if you pass out.
• This medicine is not approved for use in children younger than 18 years of age. Talk with the doctor.
• If you are over the age of 60, use this medicine (moxifloxacin tablets) with care. You could have more side effects.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach.
• Loose stools (diarrhea).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Moxifloxacin Hydrochloride Tablets

Pale red, capsule-shaped, film-coated tablets imprinted with "400" on one side containing moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin).

Antacids, Sucralfate, Multivitamins and other Products Containing Multivalent Cations

Fluoroquinolones, including moxifloxacin hydrochloride tablets, form chelates with alkaline earth and transition metal cations. Oral administration of moxifloxacin hydrochloride tablets with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as didanosine buffered tablets for oral suspension or the pediatric powder for oral solution, may substantially interfere with the absorption of moxifloxacin hydrochloride, resulting in systemic concentrations considerably lower than desired. Therefore, moxifloxacin hydrochloride tablets should be taken at least 4 hours before or 8 hours after these agents [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Warfarin

Fluoroquinolones, including moxifloxacin hydrochloride tablets, have been reported to enhance the anticoagulant effects of warfarin or its derivatives in the patient population. In addition, infectious disease and its accompanying inflammatory process, age, and general status of the patient are risk factors for increased anticoagulant activity. Therefore the prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if Moxifloxacin hydrochloride tablets are administered concomitantly with warfarin or its derivatives [see Adverse Reactions (6.2) and Clinical Pharmacology (12.3)].

Antidiabetic Agents

Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones, including moxifloxacin hydrochloride, and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered. If a hypoglycemic reaction occurs, moxifloxacin hydrochloride tablets should be discontinued and appropriate therapy should be initiated immediately [see Warnings and Precautions (5.11) and Adverse Reactions (6.1)].

Nonsteroidal Anti-Inflammatory Drugs

The concomitant administration of a nonsteroidal anti-inflammatory drug (NSAID) with a fluoroquinolone, including moxifloxacin hydrochloride tablets, may increase the risks of CNS stimulation and convulsions [see Warnings and Precautions (5.4)].

Drugs that Prolong QT

There is limited information available on the potential for a pharmacodynamic interaction in humans between moxifloxacin hydrochloride and other drugs that prolong the QTc interval of the electrocardiogram. Sotalol, a Class III antiarrhythmic, has been shown to further increase the QTc interval when combined with high doses of intravenous moxifloxacin hydrochloride in dogs. Therefore, moxifloxacin hydrochloride tablets should be avoided with Class IA and Class III antiarrhythmics [see Warnings and Precautions, (5.6) and Nonclinical Toxicology (13.2)].

Pregnancy

Risk Summary

There are no available human data establishing a drug associated risk with the use of moxifloxacin.

Based on animal studies with moxifloxacin, Moxifloxacin hydrochloride tablets may cause fetal harm. Moxifloxacin was not teratogenic when administered to pregnant rats (IV and oral), rabbits (IV), and monkeys (oral) at exposures that were 0.25–2.5 times of those at the human clinical dose (400 mg/day moxifloxacin hydrochloride). However, when moxifloxacin was administered to rats and rabbits during pregnancy and throughout lactation (rats only) at doses associated with maternal toxicity, decreased neonatal body weights, increased incidence of skeletal variations (rib and vertebra combined), and increased fetal loss were observed ( see Data). Advise pregnant women of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Animal Data

Animal reproductive and development studies were done in rats, rabbits and cynomolgus macaques. Moxifloxacin was not teratogenic when administered to pregnant rats during organogenesis (gestation days 6 to 17) 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 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 (Gestation days 6 to 17). There was no evidence of teratogenicity at intravenous doses as high as 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) in pregnant rats during organogenesis (Gestation days 6 to 17). 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 (gestation days 6 to 20) 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 in rabbits. 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 macaques were given oral doses as high as 100 mg/kg/day (2.5 times the maximum recommended human dose based upon systemic exposure) during organogenesis (gestation days 20 to 50). An increased incidence of smaller fetuses was observed at 100 mg/kg/day in macaques. In a pre- and postnatal development study conducted in rats given oral doses from Gestation day 6, throughout gestation and rearing to Postpartum day 21, effects observed at 500 mg/kg/day (0.24 times the maximum recommended human dose based on systemic exposure (AUC)) 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.

Lactation

Risk Summary

It is not known if moxifloxacin is present in human milk. Based on animal studies in rats, moxifloxacin may be excreted in human milk ( see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for moxifloxacin hydrochloride tablets and any potential adverse effects on the breastfed child from moxifloxacin hydrochloride tablets or from the underlying maternal condition.

Data

In lactating rats given a single oral dose of 4.59 mg/kg moxifloxacin (approximately 9 times less than the recommended human dose based on body surface area) 8 days postpartum, there was very low excretion of substance-related radioactivity into the milk, amounting to approximately 0.03% of the dose.

Pediatric Use

Effectiveness in pediatric patients and adolescents less than 18 years of age has not been established. Moxifloxacin hydrochloride tablets cause arthropathy in juvenile animals [see Boxed Warning, Warnings and Precautions (5.10) and Nonclinical Toxicology (13.2)].

Information describing a clinical study in cIAI in which efficacy was not demonstrated in pediatric patients is approved for Bayer Healthcare Pharmaceuticals Inc.’s AVELOX (moxifloxacin hydrochloride). However, due to Bayer Healthcare Pharmaceuticals Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as moxifloxacin hydrochloride tablets. 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 moxifloxacin hydrochloride tablets to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue moxifloxacin hydrochloride tablets and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning, and Warnings and Precautions (5.2)].

In controlled multiple-dose clinical trials, 23% of patients receiving oral moxifloxacin hydrochloride tablets 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 moxifloxacin hydrochloride tablets in patients aged 65 or older compared to younger adults.

In trials of intravenous use, 42% of moxifloxacin hydrochloride 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 moxifloxacin hydrochloride 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, moxifloxacin hydrochloride tablets 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 (5.6), Drug Interactions (7.5), and Clinical Pharmacology (12.3)].

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 (2), and Clinical Pharmacology (12.3)].

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, moxifloxacin hydrochloride tablets should be used with caution in these patients [see Warnings and Precaution (5.6) and Clinical Pharmacology, (12.3)].

Acute Bacterial Sinusitis

In a controlled double-blind study conducted in the US, moxifloxacin hydrochloride tablets (400 mg once daily for ten days) were compared with cefuroxime axetil (250 mg twice daily for ten days) for the treatment of acute bacterial sinusitis. The trial included 457 patients valid for the efficacy analysis. Clinical success (cure plus improvement) at the 7 to 21 day post-therapy test of cure visit was 90% for moxifloxacin hydrochloride and 89% for cefuroxime.

An additional non-comparative study was conducted to gather bacteriological data and to evaluate microbiological eradication in adult patients treated with moxifloxacin hydrochloride 400 mg once daily for seven days. All patients (n = 336) underwent antral puncture in this study. Clinical success rates and eradication/presumed eradication rates at the 21 to 37 day follow- up visit were 97% (29 out of 30) for Streptococcus pneumoniae, 83% (15 out of 18) for Moraxella catarrhalis, and 80% (24 out of 30) for Haemophilus influenzae.

Acute Bacterial Exacerbation of Chronic Bronchitis

Moxifloxacin hydrochloride tablets (400 mg once daily for five days) were evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared moxifloxacin hydrochloride with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients. Clinical success was assessed at 7-17 days post-therapy. The clinical success for moxifloxacin hydrochloride was 89% (222/250) compared to 89% (224/251) for clarithromycin.

Table 12: Clinical Success Rates at Follow-Up Visit for Clinically Evaluable Patients by Pathogen (Acute Bacterial Exacerbation of Chronic Bronchitis)

PATHOGEN	Moxifloxacin Hydrochloride	Clarithromycin
Streptococcus pneumoniae	16/16 (100%)	20/23 (87%)
Haemophilus influenzae	33/37 (89%)	36/41 (88%)
Haemophilus parainfluenzae	16/16 (100%)	14/14 (100%)
Moraxella catarrhalis	29/34 (85%)	24/24 (100%)
Staphylococcus aureus	15/16 (94%)	6/8 (75%)
Klebsiella pneumoniae	18/20 (90%)	10/11 (91%)

The microbiological eradication rates (eradication plus presumed eradication) in moxifloxacin hydrochloride treated patients were Streptococcus pneumoniae 100%, Haemophilus influenzae 89%, Haemophilus parainfluenzae 100%, Moraxella catarrhalis 85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae 85%.

Community Acquired Pneumonia

A randomized, double-blind, controlled clinical trial was conducted in the US to compare the efficacy of moxifloxacin hydrochloride tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 474 patients (382 of whom were valid for the efficacy analysis conducted at the 14–35 day follow-up visit). Clinical success for clinically evaluable patients was 95% (184/194) for moxifloxacin hydrochloride and 95% (178/188) for high dose clarithromycin.

A randomized, double-blind, controlled trial was conducted in the US and Canada to compare the efficacy of sequential intravenous/oral moxifloxacin hydrochloride 400 mg once a day for 7–14 days to an intravenous/oral fluoroquinolone control (trovafloxacin or levofloxacin) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 516 patients, 362 of whom were valid for the efficacy analysis conducted at the 7-30 day post-therapy visit. The clinical success rate was 86% (157/182) for moxifloxacin hydrochloride therapy and 89% (161/180) for the fluoroquinolone comparators.

An open-label ex-US study that enrolled 628 patients compared moxifloxacin hydrochloride to sequential intravenous/oral amoxicillin/clavulanate (1.2 gram intravenously every 8 hours/625 mg orally every 8 hours) with or without high-dose intravenous/oral clarithromycin (500 mg twice a day). The intravenous formulations of the comparators are not FDA approved. The clinical success rate at Day 5–7 for moxifloxacin hydrochloride therapy was 93% (241/258) and demonstrated superiority to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.9%, 13.2%)]. The clinical success rate at the 21–28 days post-therapy visit for moxifloxacin hydrochloride was 84% (216/258), which also demonstrated superiority to the comparators (74%, 208/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.6%, 16.3%)].

The clinical success rates by pathogen across four CAP studies are presented in Table 13.

Table 13: Clinical Success Rates By Pathogen (Pooled CAP Studies)

PATHOGEN	Moxifloxacin Hydrochloride
Streptococcus pneumoniae	80/85	(94%)
Staphylococcus aureus	17/20	(85%)
Klebsiella pneumoniae	11/12	(92%)
Haemophilus influenzae	56/61	(92%)
Chlamydophila pneumoniae	119/128	(93%)
Mycoplasma pneumoniae	73/76	(96%)
Moraxella catarrhalis	11/12	(92%)

Community Acquired Pneumonia caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP) 2

Moxifloxacin hydrochloride was effective in the treatment of community acquired pneumonia (CAP) caused by multi-drug resistant Streptococcus pneumoniae MDRSP 2 isolates. Of 37 microbiologically evaluable patients with MDRSP isolates, 35 patients (95%) achieved clinical and bacteriological success post-therapy. The clinical and bacteriological success rates based on the number of patients treated are shown in Table 14.

Table 14: Clinical and Bacteriological Success Rates for Moxifloxacin Hydrochloride-Treated MDRSP CAP Patients (Population: Valid for Efficacy)

Screening Susceptibility	Clinical Success		Bacteriological Success
	n/N *	%	n/N †	%
* n = number of patients successfully treated; N = number of patients with MDRSP (from a total of 37 patients) † n = number of patients successfully treated (presumed eradication or eradication); N = number of patients with MDRSP (from a total of 37 patients) ‡ One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate. § Azithromycin, clarithromycin, and erythromycin were the macrolide antimicrobials tested.
Penicillin-resistant	21/21	100% ‡	21/21	100% ‡
2 nd generation cephalosporin-resistant	25/26	96% ‡	25/26	96% ‡
Macrolide-resistant §	22/23	96%	22/23	96%
Trimethoprim/sulfamethoxazole-resistant	28/30	93%	28/30	93%
Tetracycline-resistant	17/18	94%	17/18	94%

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 15.

Table 15: Clinical Success Rates and Microbiological Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)

S. pneumoniae with MDRSP	Clinical Success	Bacteriological Eradication Rate
* One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.
Resistant to 2 antimicrobials	12/13 (92.3 %)	12/13 (92.3 %)
Resistant to 3 antimicrobials	10/11 (90.9 %) *	10/11 (90.9 %) *
Resistant to 4 antimicrobials	6/6 (100%)	6/6 (100%)
Resistant to 5 antimicrobials	7/7 (100%) *	7/7 (100%) *
Bacteremia with MDRSP	9/9 (100%)	9/9 (100%)

2 MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Uncomplicated Skin and Skin Structure Infections

A randomized, double-blind, controlled clinical trial conducted in the US compared the efficacy of moxifloxacin hydrochloride 400 mg once daily for seven days with cephalexin HCl 500 mg three times daily for seven days. The percentage of patients treated for uncomplicated abscesses was 30%, furuncles 8%, cellulitis 16%, impetigo 20%, and other skin infections 26%.

Adjunctive procedures (incision and drainage or debridement) were performed on 17% of the moxifloxacin hydrochloride treated patients and 14% of the comparator treated patients. Clinical success rates in evaluable patients were 89% (108/122) for moxifloxacin hydrochloride and 91% (110/121) for cephalexin HCl.

Complicated Skin and Skin Structure Infections

Two randomized, active controlled trials of cSSSI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential intravenous/oral moxifloxacin hydrochloride 400 mg once a day for 7-14 days to an intravenous/oral beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 617 patients, 335 of which were valid for the efficacy analysis. A second open-label International study compared moxifloxacin hydrochloride 400 mg once a day for 7-21 days to sequential intravenous/oral beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 804 patients, 632 of which were valid for the efficacy analysis. Surgical incision and drainage or debridement was performed on 55% of the moxifloxacin hydrochloride treated and 53% of the comparator treated patients in these studies and formed an integral part of therapy for this indication. Success rates varied with the type of diagnosis ranging from 61% in patients with infected ulcers to 90% in patients with complicated erysipelas. These rates were similar to those seen with comparator drugs. The overall success rates in the evaluable patients and the clinical success by pathogen are shown in Tables 16 and 17.

Table 16: Overall Clinical Success Rates in Patients with Complicated Skin and Skin Structure Infections

Study	Moxifloxacin Hydrochloride n/N (%)	Comparator n/N (%)	95% Confidence Interval *
* of difference in success rates between Moxifloxacin and comparator (Moxifloxacin-comparator)
North America	125/162 (77.2%)	141/173 (81.5%)	(-14.4%, 2%)
International	254/315 (80.6%)	268/317 (84.5%)	(-9.4%, 2.2%)

Table 17: Clinical Success Rates by Pathogen in Patients with Complicated Skin and Skin Structure Infections

Pathogen	Moxifloxacin Hydrochloride n/ N (%)	Comparator n/N (%)
* methicillin susceptibility was only determined in the North American Study
Staphylococcus aureus (methicillin-susceptible isolates) *	106/129 (82.2%)	120/137 (87.6%)
Escherichia coli	31/38 (81.6 %)	28/33 (84.8 %)
Klebsiella pneumoniae	11/12 (91.7 % )	7/10 (70%)
Enterobacter cloacae	9/11 (81.8%)	4/7 (57.1%)

Complicated Intra-Abdominal Infections

Two randomized, active controlled trials of cIAI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential intravenous/oral moxifloxacin hydrochloride 400 mg once a day for 5-14 days to intravenous/piperacillin/tazobactam followed by oral amoxicillin/clavulanic acid in the treatment of patients with cIAI, including peritonitis, abscesses, appendicitis with perforation, and bowel perforation. This study enrolled 681 patients, 379 of which were considered clinically evaluable. A second open-label international study compared moxifloxacin hydrochloride 400 mg once a day for 5-14 days to intravenous ceftriaxone plus intravenous metronidazole followed by oral amoxicillin/clavulanic acid in the treatment of patients with cIAI. This study enrolled 595 patients, 511 of which were considered clinically evaluable. The clinically evaluable population consisted of subjects with a surgically confirmed complicated infection, at least 5 days of treatment and a 25-50 day follow-up assessment for patients at the Test of Cure visit. The overall clinical success rates in the clinically evaluable patients are shown in Table 18.

Table 18: Clinical Success Rates in Patients with Complicated Intra-Abdominal Infections

Study	Moxifloxacin Hydrochloride n/ N (%)	Comparator n/N (%)	95% Confidence Interval *
* of difference in success rates between moxifloxacin hydrochloride and comparator (moxifloxacin hydrochloride-comparator) † Excludes 2 patients who required additional surgery within the first 48 hours. ‡ NA - not applicable
North America (overall)	146/183 (79.8%)	153/196 (78.1%)	(-7.4%, 9.3%)
Abscess	40/57 (70.2%)	49/63 (77.8%) †	NA ‡
Non-abscess	106/126 (84.1%)	104/133 (78.2%)	NA
International (overall)	199/246 (80.9%)	218/265 (82.3%)	(-8.9%, 4.2%)
Abscess	73/93 (78.5%)	86/99 (86.9%)	NA
Non-abscess	126/153 (82.4%)	132/166 (79.5%)	NA

Plague

Efficacy studies of moxifloxacin hydrochloride could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals and supportive pharmacokinetic data in adult humans and animals.

A randomized, blinded, placebo-controlled study was conducted in an African Green Monkey (AGM) animal model of pneumonic plague. Twenty AGM (10 males and 10 females) were exposed to an inhaled mean (± SD) dose of 100 ± 50 LD 50 (range 92 to 127 LD 50) of Yersinia pestis (CO92 strain) aerosol. The minimal inhibitory concentration (MIC) of moxifloxacin for the Y. pestis strain used in this study was 0.06 mcg/mL. Development of sustained fever for at least 4 hours duration was used as the trigger for the initiation of 10 days of treatment with either a humanized regimen of moxifloxacin or placebo. All study animals were febrile and bacteremic with Y. pestis prior to the initiation of study treatment. Ten of 10 (100%) of the animals receiving the placebo succumbed to disease between 83 to 139 h (mean 115 ± 19 hours) post treatment. Ten of 10 (100%) moxifloxacin-treated animals survived for the 30-day period after completion of the study treatment. Compared to the placebo group, mortality in the moxifloxacin group was significantly lower (difference in survival: 100% with a two-sided 95% exact confidence interval [66.3%, 100%], p-value<0.0001).

The mean plasma concentrations of moxifloxacin associated with a statistically significant improvement in survival over placebo in an AGM model of pneumonic plague are reached or exceeded in human adults receiving the recommended oral and intravenous dosage regimens. The mean (± SD) peak plasma concentration (C max) and total plasma exposure defined as the area under the plasma concentration-time curve (AUC) in human adults receiving 400 mg intravenously were 3.9 ±0.9 mcg/mL and 39.3 ± 8.6 mcg∙h/mL, respectively [see Clinical Pharmacology (12.3)] . The mean (± SD) peak plasma concentration and AUC 0-24 in AGM following one- day administration of a humanized dosing regimen simulating the human AUC 0-24 at a 400 mg dose were 4.4 ± 1.5 mcg/mL and 22 ± 8.0 mcg∙h/mL, respectively.

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

Serious Adverse Reactions

Advise patients to stop taking moxifloxacin hydrochloride tablets if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

Inform patients of the following serious adverse reactions that have been associated with moxifloxacin hydrochloride tablets or other fluoroquinolone use:

• Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of moxifloxacin hydrochloride tablets and may occur together in the same patient. Inform patients to stop taking moxifloxacin hydrochloride tablets immediately if they experience an adverse reaction and to call their healthcare provider.
• Tendinitis and Tendon Rupture: 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 moxifloxacin hydrochloride tablets treatment. Symptoms may be irreversible. 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.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with moxifloxacin hydrochloride tablets use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue moxifloxacin hydrochloride tablets and tell them to contact their physician.
• Central nervous system effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure) : Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including moxifloxacin hydrochloride tablets. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to moxifloxacin hydrochloride tablets before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions: Inform patients that moxifloxacin hydrochloride tablets can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking moxifloxacin hydrochloride tablets. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
• 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, instruct patients to contact their physician as soon as possible.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, instruct them to 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, instruct patients to contact their physician.
• 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 moxifloxacin hydrochloride tablets and consult a physician.

Antibacterial Resistance

Inform patients that antibacterial drugs including moxifloxacin hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When moxifloxacin hydrochloride tablets are 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 moxifloxacin hydrochloride tablets or other antibacterial drugs in the future.

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

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

Inform patients that moxifloxacin hydrochloride 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.

Plague Studies

Inform patients given moxifloxacin hydrochloride 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.

To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395, or go to www.bpirx.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.