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)and 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)] . Levofloxacin 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)].
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 ( 5.12) and 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.h/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.
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) and 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)]. Levofloxacin 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 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 (≥ 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.
Levofloxacin Tablets, USP are supplied as 250, 500, and 750 mg capsule-shaped, coated tablets. Levofloxacin tablets, USP are packaged in bottles and in unit-dose blister strips in the following configurations:
Levofloxacin tablets, USP 250 mg are light pink colored, capsule-shaped, film-coated tablets, debossed with “250” on one side and “1082” on the other side.
Bottles of 50 NDC 13668-082-50
Bottles of 100 NDC 13668-082-01
Bottles of 500 NDC 13668-082-05
100 Unit dose tablets NDC 13668-082-74
Levofloxacin tablets, USP 500 mg are brick red colored, capsule-shaped, film-coated tablets, debossed with “83” on one side and plain on the other side.
Bottles of 50 NDC 13668-083-50
Bottles of 100 NDC 13668-083-01
Bottles of 500 NDC 13668-083-05
100 Unit dose tablets NDC 13668-083-74
Levofloxacin tablets, USP 750 mg are white to off-white colored, capsule-shaped, film-coated tablets, debossed with “750” on one side and “1084” on the other side.
Bottles of 20 NDC 13668-084-21
Bottles of 50 NDC 13668-084-50
Bottles of 100 NDC 13668-084-01
Bottles of 500 NDC 13668-084-05
100 Unit dose tablets NDC 13668-084-74
Levofloxacin tablets should be stored at 20° to 25°C (68° to 77°); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Dispense in tight, light-resistant container with a child-resistant closure.
Advise the patients to read the FDA-approved patient labeling (Medication Guide)
Serious Adverse Reactions
Advise patients to stop taking levofloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.
Inform patients of the following serious adverse reactions that have been associated with levofloxacin or other fluoroquinolone use:
• Disabling and Potentially Irreversible Serious Adverse Reactions That May Occur Together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of levofloxacin and may occur together in the same patient. Inform patients to stop taking levofloxacin immediately if they experience an adverse reaction and to call their healthcare provider.
• Tendinitis and Tendon Rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue levofloxacin treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with levofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue levofloxacin and tell them to contact their physician.
• Central Nervous System Effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including levofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to levofloxacin tablets before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions: Inform patients that levofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking levofloxacin. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
• Aortic aneurysm and dissection: Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following levofloxacin therapy [see Warnings and Precautions ( 5.12) and Use in Specific Populations ( 8.4)].
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to be outdoors while using fluoroquinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.
• Lactation: Advise a lactating woman that she may pump and discard during treatment with levofloxacin and for an additional 2 days after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with levofloxacin and for an additional 2 days after the last dose [see Use in Specific Populations ( 8.2)].
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 tablets or other antibacterial drugs in the future.
Administration with Food, Fluids, and Concomitant Medications
Patients should be informed that levofloxacin tablets may be taken with or without food. The tablets should be taken at the same time each day.
Patients should drink fluids liberally while taking levofloxacin tablets to avoid formation of a highly concentrated urine and crystal formation in the urine.
Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours after oral levofloxacin tablet administration.
Drug Interactions with Insulin, Oral Hypoglycemic Agents, and Warfarin
Patients should be informed that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue levofloxacin and consult a physician.
Patients should be informed that concurrent administration of warfarin and levofloxacin has been associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical episodes of bleeding. Patients should notify their physician if they are taking warfarin, be monitored for evidence of bleeding, and also have their anticoagulation tests closely monitored while taking warfarin concomitantly.
Plague and Anthrax Studies Patients given levofloxacin for these conditions should be informed that efficacy studies could not be conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.
TORRENT PHARMACEUTICALS LTD., INDIA.
TORRENT PHARMA INC., Basking Ridge, NJ 07920.
8081458 Revised: February 2021
|MEDICATION GUIDE Levofloxacin (lee-voe-FLOX-a-sin) Tablets, USP 250 mg Tablets, 500 mg Tablets, and 750 mg Tablets|
|What is the most important information I should know about levofloxacin tablets? Levofloxacin tablets, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side effects can happen at the same time and could result in death. If you have any of the following serious side effects while you take levofloxacin tablets, you should stop taking levofloxacin tablets immediately and get medical help right away. 1. Tendon rupture or swelling of the tendon (tendinitis).|
|Tendons are tough cords of tissue that connect muscles to bones. Some tendon problems include: ○ pain ○ swelling ○ tears and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.|
|○ are over 60 years of age ○ are taking steroids (corticosteroids) ○ have had a kidney, heart or lung transplant.|
|○ physical activity or exercise ○ kidney failure ○ tendon problems in the past, such as in people with rheumatoid arthritis (RA).|
○ hear or feel a snap or pop in a tendon area ○ bruising right after an injury in a tendon area ○ unable to move the affected area or bear weight
The tendon problems may be permanent.
|2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including levofloxacin. Stop taking levofloxacin tablets immediately and talk to your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:|
|Pain Burning tingling|
|The nerve damage may be permanent. 3. Central Nervous System (CNS) effects. Mental health problems and seizures have been reported in people who take fluoroquinolone antibacterial medicines, including levofloxacin. Tell your healthcare provider if you have a history of mental health problems, including depression, or have a history of seizures before you start taking levofloxacin tablets. CNS side effects may happen as soon as after taking the first dose of levofloxacin tablet. Stop taking levofloxacin tablets immediately and talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:|
|4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like levofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start taking levofloxacin. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.|
|What are levofloxacin tablets? Levofloxacin tablets are a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include:|
|Studies of levofloxacin tablets for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. Levofloxacin tablets should not be used in people with uncomplicated urinary tract infections, acute bacterial exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment options available. Levofloxacin tablets are also used to treat children who weigh at least 66 pounds (or at least 30 kilograms) and may have breathed in anthrax germs, have plague, or been exposed to plague germs. It is not known if levofloxacin tablets are safe and effective in children under 6 months of age. The safety and effectiveness in children treated with levofloxacin tablets for more than 14 days is not known.|
|Who should not take levofloxacin tablets? Do not take levofloxacin tablets if you have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin tablets. See the end of this leaflet for a complete list of ingredients in levofloxacin tablets.|
|Before you take levofloxacin tablets, tell your healthcare provider about all of your medical conditions, including if you:|
|Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Levofloxacin tablets and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:|
|○ an antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum, iron, or zinc ○ sucralfate (Carafate®) ○ didanosine (Videx®, Videx® EC)|
|Ask your healthcare provider if you are not sure if any of your medicines are listed above. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.|
|How should I take levofloxacin tablets?|
|○ you have tendon problems. See “What is the most important information I should know about levofloxacin tablets?” ○ you have a nerve problem. See “What are the possible side effects of levofloxacin tablets?”. ○ you have a central nervous sytem problem. See “What are the possible side effects of levofloxacin tablets?”.” ○ you have a serious allergic reaction. see “What are the possible side effects of levofloxacin tablets?” ○ your healthcare provider tells you to stop taking levofloxacin tablets|
|Taking all of your levofloxacin tablets doses will help make sure that all of the bacteria are killed. Taking all of your levofloxacin tablets doses will help you lower the chance that the bacteria will become resistant to levofloxacin tablets. If your infection does not get better while you take levofloxacin tablets, it may mean that the bacteria causing your infection may be resistant to levofloxacin tablets. If your infection does not get better, call your healthcare provider. If your infection does not get better, levofloxacin tablets and other similar antibiotic medicines may not work for you in the future.|
|What should I avoid while taking levofloxacin tablets?|
|What are the possible side effects of levofloxacin tablets? Levofloxacin tablets can cause serious side effects, including:|
|Allergic reactions can happen in people taking fluoroquinolones, including levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction: ○ hives ○ trouble breathing or swallowing ○ swelling of the lips, tongue, face ○ throat tightness, hoarseness ○ rapid heartbeat ○ faint ○ skin rash Skin rash may happen in people taking levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets at the first sign of a skin rash and immediately call your healthcare provider. Skin rash may be a sign of a more serious reaction to levofloxacin tablets.|
|Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin tablets. Call your healthcare provider right away if you have unexplained symptoms such as:|
|○ nausea or vomiting ○ stomach pain ○ fever ○ weakness ○ abdominal pain or tenderness ○ itching ○ unusual tiredness ○ loss of appetite ○ light colored bowel movements ○ dark colored urine ○ yellowing of your skin or the whites of your eyes.|
|Stop taking levofloxacin tablets and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to levofloxacin tablets (a liver problem).|
|Aortic aneurysm and dissection|
|Tell your healthcare provider if you have ever been told that you have an aortic aneurysm, a swelling of the large artery that carries blood from the heart to the body. Get emergency medical help right away if you have sudden chest, stomach, or back pain.|
|Intestine infection (Clostridium difficile-associated diarrhea)|
|Clostridium difficile-associated diarrhea (CDAD)can happen with many antibiotics, including levofloxacin tablets. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. CDAD can happen 2 or more months after you have finished your antibiotic.|
|Serious heart rhythm changes (QT prolongation and torsades de pointes)|
|Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Levofloxacin tablets may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:|
|○ who are elderly ○ with a family history of prolonged QT interval ○ with low blood potassium (hypokalemia) ○ who take certain medicines to control heart rhythm (antiarrhythmics)|
|Increased chance of problems with joints and tissues around joints in children can happen. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with levofloxacin tablets.|
|People who take levofloxacin tablets and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin tablets, stop taking levofloxacin tablets and call your healthcare provider right away. Your antibiotic medicine may need to be changed.|
|Sensitivity to sunlight (photosensitivity)|
|See “What should I avoid while taking levofloxacin tablets?”|
|The most common side effects of levofloxacin tablets include:|
|○ nausea ○ headache ○ diarrhea ○ insomnia ○ constipation ○ dizziness In children 6 months and older who take levofloxacin tablets to treat anthrax disease or plague, vomiting is also common. Levofloxacin tablets may cause false-positive urine screening results for opiates when testing is done with some commercially available kits. A positive result should be confirmed using a more specific test. These are not all the possible side effects of levofloxacin tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.|
|How should I store levofloxacin tablets ?|
|General information about the safe and effective use of levofloxacin tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use levofloxacin tablets for a condition for which it is not prescribed. Do not give levofloxacin tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about levofloxacin tablets. If you would like more information about levofloxacin tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about levofloxacin tablets that is written for health professionals.|
|What are the ingredients in levofloxacin tablets? Active ingredient: levofloxacin, USP. Inactive ingredients: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. 250 mg & 500 mg levofloxacin film-coated tablets also contain synthetic ferric oxide red and synthetic ferric oxide yellow. This Medication Guide has been approved by the U.S. Food and Drug Administration. Trade marks are property of their respective owner. For more information call 1-800-912-9561.|
|Manufactured by: TORRENT PHARMACEUTICALS LTD., INDIA. Manufactured for: TORRENT PHARMA INC., Basking Ridge, NJ 07920.|
|8081459 Revised: February 2021|
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