Levofloxacin (Page 15 of 17)

14.9 Inhalational Anthrax (Post-Exposure)

The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [ see Indications and Usage ( 1.13); Dosage and Administration ( 2.1, 2.2) ].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0-24 ) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg•h/mL, respectively. The predicted steady state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [ see Clinical Pharmacology ( 12.3) ].

In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized. However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged levofloxacin therapy in adults should only be used when the benefit outweighs the risk.

In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days. Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [ see Warnings and Precautions ( 5.10), Use in Specific Populations ( 8.4) ].

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD 50 (~2.7 X 10 6) spores (range 17 to 118 LD 50 ) of B. anthracis (Ames strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected T max (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady state AUC 0-24 was 33.4 ± 3.2 mcg•hr/mL (range 30.4 to 36.0 mcg•h/mL). Mortality due to anthrax for animals that received a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P = 0.0011, 2 sided Fisher’s Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30 day drug administration period.

14.10 Plague

Efficacy studies of levofloxacin 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.

The mean plasma concentrations of levofloxacin associated with a statistically significant improvement in survival over placebo in an African green monkey model of pneumonic plague are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [ see Indications and Usage ( 1.14) , Dosage and Administration ( 2.1) , ( 2.2) ].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC 0-24 ) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg•h/mL, respectively. The predicted steady state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [ see Clinical Pharmacology ( 12.3) ].

A placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65 LD 50 (range 3 to 145 LD 50 ) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory concentration (MIC) of levofloxacin for the Y. pestis strain used in this study was 0.03 mcg/mL. Mean plasma concentrations of levofloxacin achieved at the end of a single 30 min infusion ranged from 2.84 to 3.50 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from < 0.03 to 0.06 mcg/mL. Mean (SD) AUC 0-24 was 11.9 (3.1) mcg•h/mL (range 9.50 to 16.86 mcg•h/mL). Animals were randomized to receive either a 10 day regimen of i.v. levofloxacin or placebo beginning within 6 hrs of the onset of telemetered fever (≥ 39ºC for more than 1 hour). Mortality in the levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p < 0.001, Fisher’s Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality]. One levofloxacin-treated animal was euthanized on Day 9 post-exposure to Y. pestis due to a gastric complication; it had a blood culture positive for Y. pestis on Day 3 and all subsequent daily blood cultures from Day 4 through Day 7 were negative.

15 REFERENCES

  • Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Approved Standard – 9 th ed. CLSI Document M7-A9, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, 2012.
  • CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22 nd Informational Supplement. CLSI Document M100 – S22, 2012.
  • CLSI Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard – 11 th ed. CLSI M2-A11, 2012.
  • CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – 2 nd ed. CLSI Document M45-A2, 2010.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Levofloxacin Tablets

Levofloxacin tablets are available as follows:

250 mg are available as terra cotta pink, film-coated, oval-shaped tablets, debossed with “TEVA” on one side and “7291” on the other, in bottles of 50.

500 mg are available as peach-colored, film-coated, oval-shaped tablets, debossed with “TEVA” on one side and “7292” on the other, in bottles of 50.

750 mg are available as white to off-white, film-coated, oval-shaped tablets, debossed with “TEVA” on one side and “7293” on the other, in bottles of 50.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide ( 17.6) .

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