Levaquin - Use levofloxacin

Indications for LEVAQUIN (levofloxacin tablet, film coated) refers to the medical reasons for why Levaquin is used and recommended as a treatment. Contraindications for Levaquin refers to medical situations for which Levaquin is not recommended due to side effects or other risks.

Contraindications

LEVAQUIN® is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions (5.3)].

Known hypersensitivity to LEVAQUIN® or other quinolones (4 , 5.7)

Use In Specific Populations

  • Geriatrics: Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older (5.8, 8.5, 17). May have increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use (5.2, 8.5, 17). May be more susceptible to prolongation of the QT interval. (5.11, 8.5, 17).
  • Pediatrics: Musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) seen in more LEVAQUIN®-treated patients than in comparator. Shown to cause arthropathy and osteochondrosis in juvenile animals (5.12, 8.4, 13.2). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure) (1.7 , 2.2 , 8.4 , 14.9) and plague (1.8, 2.2, 8.4, 14.10)
  • Lactation: Breastfeeding is not recommended during treatment, but a lactating woman may pump and discard breastmilk during treatment and an additional 2 days after the last dose.

pregnancy

Risk Summary

Published information from case reports, case control studies and observational studies on levofloxacin administered during pregnancy have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of levofloxacin to pregnant rats and rabbits during organogenesis at doses up to 9.4 times and 1.1 times the maximum recommended human dose (MRHD), respectively, did not result in teratogenicity. Fetal toxicity was seen in the rat study, but was absent at doses up to 1.2 times the maximum recommended human dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal Data

Levofloxacin was not teratogenic in an embryofetal development study in rats treated during organogenesis with oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the MRHD (based upon doses normalized for total body surface area). The oral dose of 810 mg/kg/day (high dose) to rats caused decreased fetal body weight and increased fetal mortality that was not seen at the next lower dose (mid-dose, 90 mg/kg/day, equivalent to 1.2 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity was limited to lower weight gain in the mid and high dose groups. No teratogenicity was observed in an embryofetal development study in rabbits dosed orally during organogenesis with doses as high as 50 mg/kg/day, which corresponds to 1.1 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity at that dose consisted of lower weight gain and decreased food consumption relative to controls and abortion in four of sixteen dams.

lactation

Risk Summary

Published literature reports that levofloxacin is present in human milk following intravenous and oral administration (see Data ). There is no information regarding effects of LEVAQUIN on milk production or the breastfed infant. Because of the potential risks of serious adverse reactions, in breastfed infants, a lactating woman may consider pumping and discarding breast milk during treatment with LEVAQUIN and an additional two days (five half-lives) after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with LEVAQUIN and for an additional two days (five half-lives) after the last dose [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ].

Data

A published literature reports that peak levofloxacin human milk concentration was 8.2 mg/L at 5 hours after dosing in a woman who received 500 mg of intravenous, followed by oral, levofloxacin daily. For an infant fed exclusively with human milk (approximately 900 ml/day), an estimated maximum daily dose of levofloxacin through breastfeeding is 5 mg (i.e., approximately 1% of maternal daily dose). The above data come from a single case and may not be generalizable to the general population of lactating women.

pediatric use

Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions (5.12) and Animal Toxicology and/or Pharmacology (13.2)].

Inhalational Anthrax (Post-Exposure)

Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied [see Indications and Usage (1.7) , Dosage and Administration (2.2) and Clinical Studies (14.9)].

Plague

Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of LEVAQUIN® 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 risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate [see Indications and Usage (1.8) , Dosage and Administration (2.2) and Clinical Studies (14.10)].

Safety and effectiveness of LEVAQUIN® in pediatric patients below the age of six months have not been established.

Pharmacokinetics following intravenous administration

The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.9)].

Dosage in Pediatric Patients with Inhalational Anthrax or Plague

For the recommended LEVAQUIN® tablet dosage in pediatric patients with inhalational anthrax or plague, see Dosage and Administration (2.2). LEVAQUIN® Tablets cannot be administered to pediatric patients who weigh less than 30 kg because of the limitations of the available strengths. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg.

Adverse Reactions

In clinical trials, 1534 pediatric patients (6 months to 16 years of age) were treated with oral and intravenous LEVAQUIN®. Pediatric patients 6 months to 5 years of age received LEVAQUIN® 10 mg/kg twice a day and pediatric patients greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days. LEVAQUIN® Tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration (2.2)].

A subset of pediatric patients in the clinical trials (1340 LEVAQUIN®-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Pediatric patients treated with LEVAQUIN® had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. LEVAQUIN® Tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration (2.2)].

Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial
Follow-up Period LEVAQUIN®
N = 1340
Non-Fluoroquinolone
Non-Fluoroquinolone: ceftriaxone, amoxicillin/clavulanate, clarithromycin

N = 893

p-value
2-sided Fisher's Exact Test
60 days 28 (2.1%) 8 (0.9%) p = 0.038
1 year
There were 1199 LEVAQUIN ®-treated and 804 non-fluoroquinolone-treated pediatric patients who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all pediatric patients enrolled regardless of whether they completed the 1-year evaluation visit.
46 (3.4%) 16 (1.8%) p = 0.025

Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) LEVAQUIN®-treated pediatric patients and most were treated with analgesics. The median time to resolution was 7 days for LEVAQUIN®-treated pediatric patients and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No pediatric patient had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.

Vomiting and diarrhea were the most frequently reported adverse reactions, occurring in similar frequency in the LEVAQUIN®-treated and non-fluoroquinolone-treated pediatric patients.

In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience [see Adverse Reactions (6)] may also be expected to occur in pediatric patients.

geriatric use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as LEVAQUIN®. 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 LEVAQUIN® to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue LEVAQUIN® and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning ; Warnings and Precautions (5.2) ; and Adverse Reactions (6.3)].

In Phase 3 clinical trials, 1,945 LEVAQUIN®-treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with LEVAQUIN®. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.8)].

Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions (5.9) ].

Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using LEVAQUIN® with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.11)].

The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration. However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

renal impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (creatinine clearance < 50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of LEVAQUIN® are not required following hemodialysis or CAPD [see Dosage and Administration (2.3)].

hepatic impairment

Pharmacokinetic studies in patients with hepatic impairment have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

This drug label information is as submitted to the Food and Drug Administration (FDA) and is intended for informational purposes only. If you think you may have a medical emergency, immediately call your doctor or dial 911. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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