Drug Safety-related Labeling Changes (SrLC)

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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.

CIPRO XR (NDA-021473)

(CIPROFLOXACIN; CIPROFLOXACIN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/08/2020 (SUPPL-42)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to label)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Risk Summary

Published literature reports that ciprofloxacin is present in human milk following intravenous and oral administration. There is no information regarding effects of CIPRO on milk production or the breastfed infant. Because of the potential risk of serious adverse reactions in breastfed infants, including arthropathy shown in juvenile animal studies, for most indications a lactating woman may consider pumping and discarding breast milk during treatment with CIPRO and an additional two days (five half-lives) after the last dose.

Alternatively, advise a woman that breastfeeding is not recommended during treatment with CIPRO and for an additional two days (five half-lives) after the last dose.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Adverse Reactions

Advise patients to stop taking CIPRO XR 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 CIPRO XR or other fluoroquinolone use:

Lactation: Advise a woman that breastfeeding is not recommended during treatment with Cipro and for an additional 2 days after the last dose. Alternatively, a woman may pump and discard during treatment and for additional 2 days after the last dose.

Administration Instructions

Inform patients that CIPRO XR may be taken with or without food.

Inform patients to drink fluids liberally while taking CIPRO XR to avoid formation of a highly concentrated urine and crystal formation in the urine.

Inform patients that 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 six hours after CIPRO XR administration. CIPRO XR should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, CIPRO XR may be taken with a meal that contains these products

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.

Medication Guide

(Extensive changes; please refer to label)

03/05/2020 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

Clostridioides difficile-Associated Diarrhea

(Section title revised)

(Additions and/or revisions underlined)

Clostridioides difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CIPRO XR, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

6 Adverse Reactions

(Additions and/or revisions underlined)

Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.11)]

8 Use in Specific Populations

Geriatric Use

(Additions and/or revisions underlined)

Patients should be informed of this potential side effect and advised to discontinue CIPRO XR 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 (6.2)].

Lactation

(PLLR conversion. Please refer to label for complete information.)

Pregnancy

(PLLR conversion. Please refer to label for complete information.)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Extensive changes; please refer to label)

Patient Counseling Information

Lactation: Advise a woman that breastfeeding is not recommended during treatment with Cipro and for an additional 2 days after the last dose. Alternatively, a woman may pump and discard during treatment and for additional 2 days after the last dose [see Use in Specific Populations (8.2)].

05/03/2019 (SUPPL-40)

Approved Drug Label (PDF)

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 CIPRO XR for use only when there are no alternative antibacterial treatments available.

6 Adverse Reactions

(additions 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 CIPRO? CIPRO 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.

…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Aortic aneurysm and dissection: Inform patients to seek emergency medical care if they experience sudden chest, stomach, or back pain.

10/18/2018 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.18 Blood Glucose Disturbances

(Additions and/or revisions are underlined)

Fluoroquinolones, including CIPRO XR, 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 (for example, 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 CIPRO XR, discontinue CIPRO XR and initiate appropriate therapy immediately.

5.4 Central Nervous System Effects

(Additions and/or revisions are underlined)

Psychiatric Adverse Reactions

Fluoroquinolones, including CIPRO XR, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression, or self-injurious behavior such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving CIPRO to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care.

Central Nervous System Adverse Reactions

Fluoroquinolones, including CIPRO XR, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), dizziness, and tremors. CIPRO, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. As with all fluoroquinolones, use CIPRO with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). If seizures occur, discontinue CIPRO and institute appropriate care.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Serious Adverse Reactions

Blood Glucose Disturbances: Inform the patients that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue CIPRO XR and consult a physician.

Medication Guide

(Additions and/or revisions are underlined)

What are the possible side effects of CIPRO?

Changes in blood sugar

People who take CIPRO 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 CIPRO, stop taking CIPRO and call your healthcare provider right away. Your antibiotic medicine may need to be changed.

07/26/2017 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.15 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes

(addition underlined)

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine and zolpidem) results in increased plasma concentrations of the co-administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drug.

7 Drug Interactions

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of CIPRO XR with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug.

(please refer to Table 4 in label- zolpidem added to the list of drugs that are affected by and affecting CIPRO)

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

Safety and effectiveness of CIPRO XR in pediatric patients and adolescents less than 18 years of age have not been established. Ciprofloxacin causes arthropathy (arthralgia, arthritis) in juvenile animals. CIPRO XR is not indicated for pediatric patients.

07/26/2016 (SUPPL-37)

Approved Drug Label (PDF)

Boxed Warning

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones, including CIPRO®, 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 CIPRO immediately and avoid the use of fluoroquinolones, including CIPRO, in patients who experience any of these serious adverse reactions. Fluoroquinolones, including CIPRO, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis.

Because fluoroquinolones, including CIPRO, have been associated with serious adverse reactions, reserve CIPRO 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 CIPRO, 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 CIPRO. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
Discontinue CIPRO immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including CIPRO, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Peripheral Neuropathy (new sentences added)

Fluoroquinolones, including CIPRO, have been associated with an increased risk of peripheral neuropathy. Cases of sensory…
…minimize the development of an irreversible condition…Avoid fluoroquinolones, including CIPRO, in patients who have previously experienced peripheral neuropathy.

Tendinitis and Tendon Rupture replaces Tendinopathy

Fluoroquinolones, including CIPRO, 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 CIPRO, 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 CIPRO immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including CIPRO, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.

6 Adverse Reactions

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

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)

What is the most important information I should know about CIPRO?

Tendon rupture or swelling of the tendon (tendinitis).

Stop taking CIPRO immediately and get medical help right away… (revised)
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 CIPRO. (addition)

What is CIPRO?

CIPRO 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.
CIPRO 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.

Before you take CIPRO, tell your healthcare provider if you:

have a disease that causes muscle weakness (myasthenia gravis); CIPRO should not be used in patients who have a known history of myasthenia gravis.
have nerve problems; CIPRO should not be used in patients who have a history of a nerve problem called peripheral neuropathy.

How should I take CIPRO?

Do not skip any doses of CIPRO, 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 CIPRO?”
you have central nervous system problems. See “What is the most important information I should know about CIPRO?”

PCI - Serious Adverse Reactions

Advise patients to stop taking CIPRO 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 CIPRO 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 CIPRO and may occur together in the same patient. Inform patients to stop taking CIPRO immediately if they experience an adverse reaction and to call their healthcare provider. (addition)
Tendinitis and tendon rupture replaces Tendon Disorders