Levofloxacin (Page 9 of 17)

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 ( 5.2) ; 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 ( 5.8) ].

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 torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions ( 5.10) ].

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 oflevofloxacin: 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 USP is a synthetic broad-spectrum antibacterial agent for oral and intravenous 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 USP

Structure
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The molecular formula is C 18 H 20 FN 3 O 4 •½ H 2 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, USP is essentially constant (approximately 100 mg/mL). Levofloxacin USP 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 USP 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, USP

Levofloxacin USP are available as film-coated tablets and contain the following inactive ingredients:

  • 250 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red iron oxide.
  • 500 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red and yellow iron oxides.
  • 750 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80.

USP dissolution test 4.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

The mean ±SD pharmacokinetic parameters of levofloxacin determined under single and steady-state conditions following oral tablet, oral solution, or intravenous (IV) doses of levofloxacin are summarized in Table 8.

Table 8: Mean ±SD Levofloxacin PK Parameters

Regimen C max (mcg/mL) T max (h) AUC (mcg·h/mL) CL/F 1 (mL/min) Vd/F 2 (L) T 1/2 (h) CL R (mL/ min)
Single dose
250 mg oral tablet 3 2.8 ± 0.4 1.6 ± 1.0 27.2 ± 3.9 156 ± 20 ND 7.3 ± 0.9 142 ± 21
500 mg oral tablet 3* 5.1 ± 0.8 1.3 ± 0.6 47.9 ± 6.8 178 ± 28 ND 6.3 ± 0.6 103 ± 30
500 mg oral solution 12 5.8 ± 1.8 0.8 ± 0.7 47.8 ± 10.8 183 ± 40 112 ± 37.2 7.0 ± 1.4 ND
500 mg IV 3 6.2 ± 1.0 1.0 ± 0.1 48.3 ± 5.4 175 ± 20 90 ± 11 6.4 ± 0.7 112 ± 25
750 mg oral tablet 5* 9.3 ± 1.6 1.6 ± 0.8 101 ± 20 129 ± 24 83 ± 17 7.5 ± 0.9 ND
750 mg IV 5 11.5 ± 4.0 4 ND 110 ± 40 126 ± 39 75 ± 13 7.5 ± 1.6 ND
Multiple dose
500 mg every 24h oral tablet 3 5.7 ± 1.4 1.1 ± 0.4 47.5 ± 6.7 175 ± 25 102 ± 22 7.6 ± 1.6 116 ± 31
500 mg every 24h IV 3 6.4 ± 0.8 ND 54.6 ± 11.1 158 ± 29 91 ± 12 7.0 ± 0.8 99 ± 28
500 mg or 250 mg every 24h IV, patients with bacterial infection 6 8.7± 4.0 7 ND 72.5 ± 51.2 7 154 ± 72 111 ± 58 ND ND
750 mg every 24h oral tablet 5 8.6 ± 1.9 1.4 ± 0.5 90.7 ± 17.6 143 ± 29 100 ± 16 8.8 ± 1.5 116 ± 28
750 mg every 24h IV 5 12.1 ± 4.1 4 ND 108 ± 34 126 ± 37 80 ± 27 7.9 ± 1.9 ND
500 mg oral tablet single dose, effects of gender and age:
Male 8 5.5 ± 1.1 1.2 ± 0.4 54.4 ± 18.9 166 ± 44 89 ± 13 7.5 ± 2.1 126 ± 38
Female 9 7.0 ± 1.6 1.7 ± 0.5 67.7 ± 24.2 136 ± 44 62 ± 16 6.1 ± 0.8 106 ± 40
Young 10 5.5 ± 1.0 1.5 ± 0.6 47.5 ± 9.8 182 ± 35 83 ± 18 6.0 ± 0.9 140 ± 33
Elderly 11 7.0 ± 1.6 1.4 ± 0.5 74.7 ± 23.3 121 ± 33 67 ± 19 7.6 ± 2.0 91 ± 29
500 mg oral single dose tablet, patients with renal insufficiency:
CLCR 50–80 mL/min 7.5 ± 1.8 1.5 ± 0.5 95.6 ± 11.8 88 ± 10 ND 9.1 ± 0.9 57 ± 8
CLCR 20–49 mL/min 7.1 ± 3.1 2.1 ± 1.3 182.1 ± 62.6 51 ± 19 ND 27 ± 10 26 ± 13
CLCR <20 mL/min 8.2 ± 2.6 1.1 ± 1.0 263.5 ± 72.5 33 ± 8 ND 35 ± 5 13 ± 3
Hemodialysis 5.7 ± 1.0 2.8 ± 2.2 ND ND ND 76 ± 42 ND
CAPD 6.9 ± 2.3 1.4 ± 1.1 ND ND ND 51 ± 24 ND

1 clearance /bioavaibility
2 volume of distribution/bioavailability
3 healthy males 18–53 years of age
4 60 min infusion for 250 mg and 500 mg doses, 90 min infusion for 750 mg dose
5 healthy male and female subjects 18–54 years of age
6 500 mg every 48h for patients with moderate renal impairment (CLCR 20–50 mL/min) and infections of the respiratory tract or skin
7 dose-normalized values (to 500 mg dose), estimated by population pharmacokinetic modeling
8 healthy males 22–75 years of age
9 healthy females 18–80 years of age
10 young healthy male and female subjects 18–36 years of age
11 healthy elderly male and female subjects 66–80 years of age
12 healthy males and females 19–55 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;
ND=not determined.

Absorption

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of levofloxacin from a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of levofloxacin to healthy volunteers, the mean ±SD peak plasma concentration attained was 6.2 ±1.0 mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ±4.0 mcg/mL after a 750 mg dose infused over 90 minutes. Levofloxacin Oral Solution and Tablet formulations are bioequivalent.

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-daily dosage regimen. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 ±1.4 and 0.5 ±0.2 mcg/mL after the 500 mg doses, and 8.6 ±1.9 and 1.1 ±0.4 mcg/mL after the 750 mg doses, respectively. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4±0.8 and 0.6 ±0.2 mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3±0.71 mcg/mL after the 750 mg doses, respectively. Oral administration of a 500 mg dose of levofloxacin tablets with food prolongs the time to peak concentration by approximately 1 hour and decreases the peak concentration by approximately 14% following tablet and approximately 25% following oral solution administration. Therefore, Levofloxacin Tablets can be administered without regard to food.
The plasma concentration profile of levofloxacin after IV administration is similar and comparable in extent of exposure (AUC) to that observed for Levofloxacin Tablets when equal doses (mg/mg) are administered. Therefore, the oral and IV routes of administration can be considered interchangeable (see Figure 2 and Figure 3).
Figure 2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg

figure-2
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Figure 3: Mean Levofloxacin Plasma Concentration vs. Time Profile: 500 mg

figure-3
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Distribution

The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and 500 mg doses of levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5- fold higher than plasma concentrations and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral dose.

In vitro , over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.

Metabolism

Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.
Excretion

Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.
Geriatric

There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects’ differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of levofloxacin to healthy elderly subjects (66 – 80 years of age), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary [See Use in Specific Populations ( 8.5) ].

Pediatrics

The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in pediatric patients ranging in age from 6 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. Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC 0-24 and C max ) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours.

Gender

There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects’ differences in creatinine clearance are taken into consideration.

Following a 500 mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustment based on gender alone is not necessary.

Race

The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.

Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in adult 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) , Use in Specific Populations ( 8.6) ].

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 [See Use in Specific Populations ( 8.7) ]

Bacterial Infection

The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.

Drug-Drug Interactions

The potential for pharmacokinetic drug interactions between levofloxacin and antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [see Drug Interactions ( 7) ].

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