Moxifloxacin Hydrochloride (Page 9 of 11)

14.7 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 LD50 (range 92 to 127 LD50) 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 (Cmax) 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 AUC0-24 at a 400 mg dose were 4.4 ± 1.5 mcg/mL and 22 ± 8.0 mcg·h/mL, respectively.

15 REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI), Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard – Tenth Edition. CLSI Document M7-A10 [2015], CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, USA.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement , CLSI document M100-S26 [2016], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. .
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing for Infrequently Isolated or Fastidious Bacteria: Approved Guidelines—Third Edition CLSI document M45 A3 [2016], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard — Eighth Edition. CLSI document M11-A8 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Moxifloxacin hydrochloride Tablets

Moxifloxacin hydrochloride tablets are available as pink, biconvex, capsule shaped tablets containing moxifloxacin hydrochloride equivalent to 400 mg moxifloxacin. The tablet is debossed with “n” on one side and “034” on the other side.

Package	NDC Code
Bottles of 30:	40032-034-03
Bottles of 500:	40032-034-05
Cartons of 50 Unit-dose Tablets	40032-034-31

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Avoid high humidity.

17 PATIENT COUNSELING INFORMATION

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

Serious Adverse Reactions

Advise patients to stop taking moxifloxacin hydrochloride 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 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 and may occur together in the same patient. Inform patients to stop taking moxifloxacin hydrochloride 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 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 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 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. 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 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 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. 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 and consult a physician.

Antibacterial Resistance

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

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