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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.
AVELOX IN SODIUM CHLORIDE 0.8% IN PLASTIC CONTAINER (NDA-021277)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
05/06/2020 (SUPPL-62)
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions underlined)
There are no available human data establishing a drug associated risk with the use of moxifloxacin.
Based on animal studies with moxifloxacin, Avelox may cause fetal harm. Moxifloxacin did not cause fetal malformations when administered to pregnant rats (IV and oral), rabbits (IV), and monkeys (oral) at exposures that were 0.24–2.5 times of those at the human clinical dose (400 mg/day Avelox). However, when moxifloxacin was administered to rats and rabbits during pregnancy and throughout lactation (rats only) at doses associated with maternal toxicity, decreased neonatal body weights, increased incidence of skeletal variations (rib and vertebra combined), and increased fetal loss were observed (see Data). Advise pregnant women of the potential risk to the fetus.
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 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal reproductive and development studies were done in rats, rabbits and cynomolgus macaques. Moxifloxacin did not cause fetal malformations when administered to pregnant rats during organogenesis (gestation days 6 to 17) at oral doses as high as 500 mg/kg/day or 0.24 times the maximum recommended human dose based on systemic exposure (AUC), but decreased fetal body weights and slightly delayed fetal skeletal development were observed. Intravenous administration of 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) to pregnant rats resulted in maternal toxicity and a marginal effect on fetal and placental weights and the appearance of the placenta (Gestation days 6 to 17). Fetal malformations were not observed at intravenous doses as high as 80 mg/kg/day (approximately 2 times the maximum recommended human dose based on body surface area) in litters of pregnant rats that received moxifloxacin during organogenesis (Gestation days 6 to 17). Intravenous administration of 20 mg/kg/day (approximately equal to the maximum recommended human oral dose based upon systemic exposure) to pregnant rabbits during organogenesis (gestation days 6 to 20) resulted in decreased fetal body weights and delayed fetal skeletal ossification. When rib and vertebral malformations were combined, there was an increased fetal and litter incidence of these effects in rabbits. Signs of maternal toxicity in rabbits at this dose included mortality, abortions, marked reduction of food consumption, decreased water intake, body weight loss and hypoactivity. Fetal malformations were not observed when pregnant cynomolgus macaques were given oral doses as high as 100 mg/kg/day (2.5 times the maximum recommended human dose based upon systemic exposure) during organogenesis (gestation days 20 to 50). An increased incidence of smaller fetuses was observed at 100 mg/kg/day in macaques. In a pre- and postnatal development study conducted in rats given oral doses from Gestation day 6, throughout gestation and rearing to Postpartum day 21, effects observed at 500 mg/kg/day (0.24 times the maximum recommended human dose based on systemic exposure (AUC)) included slight increases in duration of pregnancy and prenatal loss, reduced pup birth weight and decreased neonatal survival. Treatment-related maternal mortality occurred during gestation at 500 mg/kg/day in this study.
(Additions and/or revisions underlined)
Risk Summary
It is not known if moxifloxacin is present in human milk. Based on animal studies in rats, moxifloxacin may be excreted in human milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATIONAdministration Instructions
Inform patients that AVELOX tablets may be taken with or without food. Advise patients drink fluids liberally.
Inform patients that AVELOX tablets should be taken at least 4 hours before or 8 hours after multivitamins (containing iron or zinc), antacids (containing magnesium or aluminum), sucralfate, or didanosine buffered tablets for oral suspension or the pediatric powder for oral solution.
Advise patients that if a dose is missed, it should be taken anytime but not later than 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next dose, the missed dose should not be taken and treatment should be continued as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.
05/03/2019 (SUPPL-61)
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 AVELOX for use only when there are no alternative antibacterial treatments available.
6 Adverse Reactions
(addition underlined)
…
Risk of Aortic Aneurysm and Dissection
…
8 Use in Specific Populations
8.5Geriatric 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 AVELOX?
…
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-60)
5 Warnings and Precautions
5.11 Blood Glucose Disturbances(Additions and/or revisions are underlined)
As with all fluoroquinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported with AVELOX. In AVELOX-treated patients, dysglycemia occurred predominantly in elderly diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, sulfonylurea) or with insulin. Severe cases of hypoglycemia resulting in coma or death have been reported. In diabetic patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs, discontinue AVELOX and initiate appropriate therapy immediately.
(Additions and/or revisions are underlined)
Psychiatric Adverse Reactions
Fluoroquinolones,including AVELOX, have been associated with an increased risk of psychiatric adverse reactions, including: convulsions and toxic psychosis, hallucinations, or paranoia; depression or suicidal thoughts or acts; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving AVELOX, discontinue AVELOX immediately and institute appropriate measures.
Central Nervous System Adverse Reactions
Fluoroquinolones, including AVELOX, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), dizziness, and tremors. As with all fluoroquinolones, use AVELOX with caution in patients with known or suspected CNS disorders (for example, severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold. These adverse reactions may occur following the first dose. If these reactions occur in patients receiving AVELOX, discontinue AVELOX immediately and institute appropriate measure.
09/27/2016 (SUPPL-57)
8 Use in Specific Populations
8.1 Pregnancy ( PLLR conversion, please refer to label)
8.2 Lactation (PLLR conversion, please refer to label)
8.4 Pediatric Use (updated)
Effectiveness in pediatric patients and adolescents less than 18 years of age has not been established. AVELOX causes arthropathy in juvenile animals. Limited information on the safety of AVELOX in 301 pediatric patients is available from the cIAI trial.
Active Controlled Trial in Complicated Intra-Abdominal Infection (cIAI)
The safety and efficacy of AVELOX in pediatric patients for the treatment of cIAI has not been demonstrated.
Pediatric patients 3 months to <18 years of age (mean age of 12 ± 4 years) were enrolled in a single randomized, doubleblind, active controlled trial in cIAI including appendicitis with perforation, abscesses and peritonitis.
Pediatric patients were randomized (2:1) to receive either AVELOX or comparator. This study enrolled 451 patients whoreceived study medication, 301 treated with moxifloxacin, and 150 with comparator. Of the 301 pediatric patients treatedwith AVELOX, 15 were below the age of 6 years and 286 were between the ages of 6–<18 years.
Patients received sequential intravenous/oral AVELOX or comparator (intravenous ertapenem followed by oralamoxicillin/clavulanate) for 5 to 14 days (mean duration was 9 days with a range of 1 to 24 days).
The overall adverse reaction profile in pediatric patients was comparable to that of adult patients. The most frequentlyoccurring adverse reactions in pediatric patients treated with AVELOX were QT prolongation 9.3% (28/301), vomiting, 6.6% (20/301) diarrhea 3.7% (11/301), arthralgia 3.0% (9/301), and phlebitis 2.7% (8/301) (see Table 5). Discontinuation of study drug due to an adverse reaction was reported in 5.3% (16/301) of AVELOX-treated patients versus 1.3% (2/150) of comparator-treated patients. The adverse reaction profile of AVELOX or comparator was similar across all age groups
studied.
Musculoskeletal adverse reactions were monitored and followed up to 5 years after the end of study treatment. The rates of musculoskeletal adverse reactions were 4.3% (13/301) in the AVELOX-treated group versus 3.3% (5/150) in the comparator-treated group. The majority of musculoskeletal adverse reactions were reported between 12 and 53 weeks after start of study treatment with complete resolution at the end of the study.
Table 5 Incidence (%) of Selected Adverse Reactions in ?2.0% of Pediatric Patients Treated with AVELOX in cIAI Clinical Trial (please refer to label)
Table 6: Clinical Response Rates at 28–42 Days After End of Treatment in Pediatric Patients with cIAI (please refer to label)
07/26/2016 (SUPPL-59)
Boxed Warning
WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS- Fluoroquinolones, including AVELOX®, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:
- Tendinitis and tendon rupture
- Peripheral neuropathy
- Central nervous system effects
- Discontinue AVELOX immediately and avoid the use of fluoroquinolones, including AVELOX, in patients who experience any of these serious adverse reactions. Fluoroquinolones, including AVELOX, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid AVELOX in patients with known history of myasthenia gravis.
- Because fluoroquinolones, including AVELOX, have been associated with serious adverse reactions, reserve AVELOX for use in patients who have no alternative treatment options for the following indications:
- 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 AVELOX, 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 AVELOX. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
- Discontinue AVELOX immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including AVELOX, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
- Disabling and Potentially Irreversible Serious Adverse Reactions (addition)
- Tendinitis and Tendon Rupture (replaces Tendon Effects)
- Fluoroquinolones, including AVELOX, 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 AVELOX, 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 AVELOX immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including AVELOX, 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 AVELOX, tell your healthcare provider if you:- have a disease that causes muscle weakness (myasthenia gravis); AVELOX should not be used in patients who have a known history of myasthenia gravis.
- have nerve problems; AVELOX should not be used in patients who have a history of a nerve problem called peripheral neuropathy
- you have nerve problems. See “What is the most important information I should know about AVELOX?”
- you have central nervous system problems. See “What is the most important information I should know about AVELOX?”
- AVELOX 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.
- AVELOX 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.
- Stop taking AVELOX 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 AVELOX. (addition)
- Advise patients to stop taking AVELOX 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 AVELOX 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 AVELOX and may occur together in the same patient. Inform patients to stop taking AVELOX immediately if they experience an adverse reaction and to call their healthcare provider. (addition)
- Tendinitis and tendon rupture replaces Tendon Disorders