Levofloxacin (Page 8 of 16)

8.5 Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as levofloxacin. 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 levofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue levofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning, Warnings and Precautions (5.1) and Adverse Reactions (6.3)].

In Phase 3 clinical trials, 1,945 levofloxacin-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 levofloxacin. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.5)].

Elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using levofloxacin 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 Torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.9)].

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)].

8.6 Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (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 levofloxacin are not required following hemodialysis or CAPD [see Dosage and Administration (2.3)].

8.7 Hepatic Impairment

Pharmacokinetic studies in hepatically impaired patients 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.

10 OVERDOSAGE

In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.

Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of levofloxacin: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors and convulsions. Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.

11 DESCRIPTION

Levofloxacin is a synthetic broad-spectrum antibacterial agent for oral administration. Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin. The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido[1,2,3-de ]-1,4-benzoxazine-6-carboxylic acid, hemihydrate.

Figure 1: The Chemical Structure of Levofloxacin
(click image for full-size original)

Figure 1: The Chemical Structure of Levofloxacin

The molecular formula is C18 H20 FN3 O4 • ½ H2 O and the molecular weight is 370.38. Levofloxacin, USP is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine.

The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant (approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range, as defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9.

Levofloxacin has the potential to form stable coordination compounds with many metal ions. This in vitro chelation potential has the following formation order: Al+3 >Cu+2 >Zn+2 >Mg+2 >Ca+2.

Excipients and Description of Dosage Forms

Levofloxacin tablets are available as film-coated tablets and contain the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polydextrose, povidone, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

The mean ± SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet doses of levofloxacin are summarized in Table 8.

Table 8: Mean ± SD Levofloxacin PK Parameters
*
clearance/bioavailability
volume of distribution/bioavailability
healthy males 18 to 53 years of age
§
Absolute bioavailability; F = 0.99 ± 0.08 from a 500 mg tablet and F = 0.99 ± 0.06 from a 750 mg tablet
healthy male and female subjects 18 to 54 years of age
#
healthy males 22 to 75 years of age
Þ
healthy females 18 to 80 years of age
ß
young healthy male and female subjects 18 to 36 years of age
à
healthy elderly male and female subjects 66 to 80 years of age
Regimen

Cmax

(mcg/mL)

Tmax

(h)

AUC

(mcg·h/mL)

CL/F *

(mL/min)

Vd/F

(L)

t1/2

(h)

CLR

(mL/min)
Single dose
250 mg oral tablet 2.8 ± 0.41.6 ± 127.2 ± 3.9156 ± 20ND7.3 ± 0.9142 ± 21
500 mg oral tablet §5.1 ± 0.81.3 ± 0.647.9 ± 6.8178 ± 28ND6.3 ± 0.6103 ± 30
750 mg oral tablet §9.3 ± 1.61.6 ± 0.8101 ± 20129 ± 2483 ± 177.5 ± 0.9ND
Multiple dose
500 mg every 24 h oral tablet 5.7 ± 1.41.1 ± 0.447.5 ± 6.7175 ± 25102 ± 227.6 ± 1.6116 ± 31
750 mg every 24 h oral tablet 8.6 ± 1.91.4 ± 0.590.7 ± 17.6143 ± 29100 ± 168.8 ± 1.5116 ± 28
500 mg oral tablet single dose, effects of gender and age:
Male #5.5 ± 1.11.2 ± 0.454.4 ± 18.9166 ± 4489 ± 137.5 ± 2.1126 ± 38
Female Þ7 ± 1.61.7 ± 0.567.7 ± 24.2136 ± 4462 ± 166.1 ± 0.8106 ± 40
Young ß5.5 ± 11.5 ± 0.647.5 ± 9.8182 ± 3583 ± 186 ± 0.9140 ± 33
Elderly à7 ± 1.61.4 ± 0.574.7 ± 23.3121 ± 3367 ± 197.6 ± 291 ± 29
500 mg oral single dose tablet, patients with renal insufficiency:

CLCR

7.5 ± 1.81.5 ± 0.595.6 ± 11.888 ± 10ND9.1 ± 0.957 ± 8

CLCR

7.1 ± 3.12.1 ± 1.3182.1 ± 62.651 ± 19ND27 ± 1026 ± 13
CLCR < 20 mL/min8.2 ± 2.61.1 ± 1263.5 ± 72.533 ± 8ND35 ± 513 ± 3
Hemodialysis5.7 ± 12.8 ± 2.2NDNDND76 ± 42ND
CAPD6.9 ± 2.31.4 ± 1.1NDNDND51 ± 24ND
ND = not determined.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.