Prescription Drug Information: Levofloxacin (Page 10 of 12)

14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-Day Treatment Regimen

To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of levofloxacin, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing levofloxacin 250 mg orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1 to 12 days post-therapy in patients with a pathogen identified at baseline.

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20.

Table 20: Bacteriological Eradication Overall (cUTI or AP) at Test-Of-Cure¹

* The mITT population included patients who had a pathogen isolated at baseline. Patients with missing response were counted as failures in this analysis. † The Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria.
	Levofloxacin 250 mg once daily for 10 days		Ciprofloxacin 500 mg twice daily for 10 days
	n/N	%	n/N	%
mITT Population *	174/209	83.3	184/219	84
Microbiologically Evaluable Population †	164/177	92.7	159/171	93

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 LD₅₀ (~2.7 x 10⁶) spores (range 17 to 118 LD₅₀ ) 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.h/mL (range 30.4 to 36 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 LD₅₀ (range 3 to 145 LD₅₀ ) 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 (≥ 39°C 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

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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.

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CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22^nd Informational Supplement. CLSI Document M100 – S22, 2012.

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CLSI Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard – 11^th ed. CLSI M2-A11, 2012.

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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

Levofloxacin tablets are supplied as 500 mg, and 750 mg octagonal, biconvex, film-coated tablets. Levofloxacin tablets are packaged in bottles in the following configurations:

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500 mg tablets: color: orange, debossing: “SZ 986” on one side.

NDC 63187-003-10, bottles of 10 tablets

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750 mg tablets: color: yellow, debossing: “SZ 987” on one side.

NDC 63187-004-10, bottles of 10 tablets

Levofloxacin tablets should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] in well-closed containers as described in the USP.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide (17.6)

17.1 Antibacterial Resistance

Antibacterial drugs including levofloxacin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When levofloxacin 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 levofloxacin or other antibacterial drugs in the future.