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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
LEVAQUIN (NDA-020634)
(LEVOFLOXACIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
06/22/2020 (SUPPL-73)
8 Use in Specific Populations
8.2 Lactation(Additions and/or revisions underlined)
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, for most indications, 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)].
However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on LEVAQUIN may be acceptable [see Dosage and Administration (2.2), Pediatric Use (8.4), and Clinical Studies (14.2)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEVAQUIN and any potential adverse effects on the breastfed child from LEVAQUIN or from the underlying maternal condition.
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions underlined)
…
Before you take LEVAQUIN, tell your healthcare provider about all of your medical conditions, including if you:
have tendon problems. LEVAQUIN should not be used in people who have a history of tendon problems.
have a problem that causes muscle weakness (myasthenia gravis). LEVAQUIN should not be used in people who have a known history of myasthenia gravis.
have a history of mental health problems, including depression.
have central nervous system problems such as seizures (epilepsy).
have nerve problems. LEVAQUIN should not be used in people who have a history of a nerve problem called peripheral neuropathy.
have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation.”
have low blood potassium (hypokalemia).
have bone problems.
have joint problems including rheumatoid arthritis (RA).
have kidney problems. You may need a lower dose of LEVAQUIN if your kidneys do not work well.
have liver problems.
have diabetes or problems with low blood sugar (hypoglycemia).
are pregnant or plan to become pregnant. It is not known if LEVAQUIN will harm your unborn child.
- are breastfeeding or plan to breastfeed. LEVAQUIN passes into your breast milk. You should not breastfeed during treatment with LEVAQUIN and for 2 days after taking your last dose of LEVAQUIN. You may pump your breast milk and throw it away during treatment with LEVAQUIN and for 2 days after taking your last dose of LEVAQUIN. If you are taking LEVAQUIN for inhalational anthrax, you and your healthcare provider should decide whether you can continue breastfeeding while taking LEVAQUIN.
…
06/28/2019 (SUPPL-71)
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion)
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.
(PLLR conversion)
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.
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(additions underlined)
…
rupture or swelling of the tendon (tendinitis).
…
Stop taking LEVAQUIN immediately and get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
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.
…
Before you take LEVAQUIN, tell your healthcare provider about all of your medical conditions, including if you:
…
have a history of mental health problems, including depression.
…
are breastfeeding or plan to breastfeed. LEVAQUIN passes into your breast milk. You should not breastfeed during treatment with LEVAQUIN and for 2 days after taking your last dose of LEVAQUIN. You may pump your breast milk and throw it away during treatment with LEVAQUIN and for 2 days after taking your last dose of LEVAQUIN.
…
LEVAQUIN may cause serious side effects, including:
...
Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take LEVAQUIN. Call your healthcare provider right away if you have unexplained symptoms such as:
…
pain or tenderness in the upper right side of your stomach-area
…
(additions underlined)
…
Lactation: Advise a lactating woman that she may pump and discard during treatment with LEVAQUIN and for an additional 2 days after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with LEVAQUIN and for an additional 2 days after the last dose.
…
05/03/2019 (SUPPL-72)
5 Warnings and Precautions
5.9 Risk of Aortic Aneurysm and Dissection(new subsection added)
Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve LEVAQUIN® for use only when there are no alternative antibacterial treatments available.
6 Adverse Reactions
6.1 Serious and Otherwise Important Adverse Reactions(addition underlined)
…
Risk of Aortic Aneurysm and Dissection
…
8 Use in Specific Populations
8.5 Geriatric Use(additions underlined)
…
Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(additions underlined)
…
What are the possible side effects of LEVAQUIN?
LEVAQUIN may cause serious side effects, including:
…
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.
…
(additions underlined)
…
Serious Adverse Reactions
…
Aortic aneurysm and dissection: Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.
…
10/18/2018 (SUPPL-70)
5 Warnings and Precautions
5.1 Central Nervous System Effects(Additions and/or revisions are underlined)
Psychiatric Adverse Reactions
Fluoroquinalones including LEVAQUIN®, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. Attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving LEVAQUIN®, discontinue LEVAQUIN® and institute appropriate measures.
Central Nervous System Adverse Reactions
Fluoroquinolones, including LEVAQUIN®, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, LEVAQUIN® should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). If these reactions occur in patients receiving LEVAQUIN®, discontinue LEVAQUIN® and institute appropriate measures.
(Additions and/or revisions are underlined)
Psychiatric Adverse Reactions
Fluoroquinalones including LEVAQUIN®, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. Attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving LEVAQUIN®, discontinue LEVAQUIN® and institute appropriate measures.
Central Nervous System Adverse Reactions
Fluoroquinolones, including LEVAQUIN®, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, LEVAQUIN® should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). If these reactions occur in patients receiving LEVAQUIN®, discontinue LEVAQUIN® and institute appropriate measures.
(Additions and/or revisions are underlined)
Fluoroquinolones, including LEVAQUIN®, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with LEVAQUIN®, discontinue LEVAQUIN® and initiate appropriate therapy immediately.
07/02/2018 (SUPPL-69)
8 Use in Specific Populations
8.4 Pediatric Use(Additions and/or revisions are underlined)
Dosage in Pediatric Patients with Inhalational Anthrax or Plague
For the recommended LEVAQUIN tablet dosage in pediatric patients with inhalational anthrax or plague. 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.
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.
(Additions and/or revisions are underlined)
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.
02/08/2017 (SUPPL-68)
5 Warnings and Precautions
5.4 Central Nervous System Effects(additions underlined)
Fluoroquinolones, including LEVAQUIN, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, toxic psychoses, increased intracranial (including pseudotumor cerebri) . Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. Suicidal thoughts, and attempted or completed suicide may also occur, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving LEVAQUIN®, discontinue LEVAQUIN and institute appropriate measures. As with other fluoroquinolones, LEVAQUIN® should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction).
6 Adverse Reactions
6.3 Postmarketing Experience(additions and revisions to Table 6, please refer to label)
Table 6 lists adverse reactions that have been identified during post-approval use of LEVAQUIN®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
07/26/2016 (SUPPL-67)
Boxed Warning
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS- Tendinitis and tendon rupture
- Peripheral neuropathy
- Central nervous system effects
- Acute exacerbation of chronic bronchitis
- Acute uncomplicated cystitis
- Acute sinusitis
5 Warnings and Precautions
Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects (addition)- Fluoroquinolones, including LEVAQUIN, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting LEVAQUIN. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
- Discontinue LEVAQUIN immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including LEVAQUIN, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
- Fluoroquinolones, including LEVAQUIN, have been associated with an increased risk of peripheral neuropathy. Cases of sensory…
- …minimize the development of an irreversible condition…Avoid fluoroquinolones, including LEVAQUIN, in patients who have previously experienced peripheral neuropathy.
- Fluoroquinolones, including LEVAQUIN, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting LEVAQUIN, or as long as several months after completion of fluoroquinolone therapy... Tendinitis and tendon rupture can occur bilaterally.
- The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Discontinue LEVAQUIN immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including LEVAQUIN, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.
6 Adverse Reactions
- Disabling and Potentially Irreversible Serious Adverse Reactions (addition)
- Tendinitis and Tendon Rupture (replaces Tendon Effects)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MG - Before you take LEVAQUIN, tell your healthcare provider if you:- have a disease that causes muscle weakness (myasthenia gravis); LEVAQUIN should not be used in patients who have a known history of myasthenia gravis.
- have nerve problems; LEVAQUIN should not be used in patients who have a history of a nerve problem called peripheral neuropathy
Do not skip any doses of LEVAQUIN, or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless:
- you have nerve problems. See “What is the most important information I should know about LEVAQUIN?”
- you have central nervous system problems. See “What is the most important information I should know about LEVAQUIN?”
- LEVAQUIN should not be used in patients with acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and sinus infections, if there are other treatment options available.
- LEVAQUIN should not be used as the first choice of antibacterial medicine to treat lower respiratory tract infections cause by a certain type of bacterial called Streptococcus pneumonia.
Tendon rupture or swelling of the tendon (tendinitis).
- Stop taking LEVAQUIN immediately and get medical help right away…
- Worsening of myasthenia gravis (a problem that causes muscle weakness). Tell your healthcare provider if you have a history of myasthenia gravis before you start taking LEVAQUIN. (addition)
- Advise patients to stop taking LEVAQUIN 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 LEVAQUIN 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 LEVAQUIN and may occur together in the same patient. Inform patients to stop taking LEVAQUIN immediately if they experience an adverse reaction and to call their healthcare provider. (addition)
- Tendinitis and tendon rupture replaces Tendon Disorders