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.

DIFLUCAN (NDA-019949)

(FLUCONAZOLE)

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

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02/12/2024 (SUPPL-72)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Extensive changes; please refer to label for complete information

6 Adverse Reactions

Newly added information:

Clinical Trials Experience in Pediatric Patients

Safety in Prophylaxis of Invasive Candida Infections in Premature infants weighing less than 750 grams at birth

In a Phase 3 clinical trial of pediatric patients (premature infants weighing less than 750 grams at birth), the incidence of intestinal perforation in infants receiving DIFLUCAN prophylaxis was higher compared to infants receiving placebo (see PRECAUTIONS: Pediatric Use).

Safety in Pediatric Patients Receiving ECMO

A cohort of 20 pediatric patients (1 day to 17 years of age) on ECMO received DIFLUCAN in a prospective, open-label, single-center safety and PK ECMO study. The adverse reaction profile of DIFLUCAN in these patients was similar to that of adult and pediatric non-ECMO patients (See PRECAUTIONS: Pediatric Use).

07/12/2023 (SUPPL-74)

Approved Drug Label (PDF)

7 Drug Interactions

Additions and/or revisions underlined:

…

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin (decreased hepatic metabolism of the statin). If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Dose reduction of statins may be needed. Refer to the statin-specific prescribing information for details.

…

Ivacaftor and fixed dose ivacaftor combinations (e.g., tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor): Coadministration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold. If used concomitantly with a moderate inhibitor of CYP3A4, such as fluconazole, a reduction in the dose of ivacaftor (or ivacaftor combination) is recommended as instructed in the ivacaftor (or ivacaftor combination) prescribing information.

…

Lurasidone: Concomitant use of moderate inhibitors of CYP3A4 such as fluconazole may increase lurasidone plasma concentrations. If concomitant use cannot be avoided, reduce the dose of lurasidone as instructed in the lurasidone prescribing information.

…

01/17/2023 (SUPPL-73)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Newly added information:

Abrocitinib: Drug interaction studies indicate that when co-administered with fluconazole (strong inhibitor of CYP2C19; moderate inhibitor of CYP2C9 and CYP3A4), the systemic exposure of abrocitinib and its active metabolites increased (See CLINICAL PHARMACOLOGY). Avoid concomitant use of abrocitinib with DIFLUCAN. Refer to the abrocitinib Prescribing Information for additional details.

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

PATIENT INFORMATION

Additions and revisions underlined:

Especially tell your healthcare provider if you take:

. . .

abrocitinib (used to treat atopic dermatitis, also known as eczema)

03/09/2022 (SUPPL-71)

Approved Drug Label (PDF)

7 Drug Interactions

Additions and revisions underlined:

Newly added information:

Ivacaftor and fixed dose ivacaftor combinations (e.g., tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor): Coadministration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold. If used concomitantly with a moderate inhibitor of CYP3A4, such as fluconazole, a

reduction in the dose of ivacaftor (or ivacaftor combination) is recommended as instructed in the ivacaftor (or ivacaftor combination) prescribing information.

Additions and revisions underlined:

Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)

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

Patient Information

Additions and revisions underlined:

Especially tell your healthcare provider if you take:

• ivacaftor or ivacaftor combinations, such as tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor, used to treat cystic fibrosis

• lurasidone used to treat schizophrenia or depression

10/25/2021 (SUPPL-70)

Approved Drug Label (PDF)

4 Contraindications

(Coadministration of terfenadine, cisapride and astemizole have been removed)

7 Drug Interactions

(Additions and/or revisions underlined)

…

Lemborexant: Concomitant administration of fluconazole increased lemborexant Cmax and AUC by approximately 1.6- and 4.2-fold, respectively which is expected to increase risk of adverse reactions, such as somnolence. Avoid concomitant use of DIFLUCAN with lemborexant.

…

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

PATIENT INFORMATION

(Extensive changes; please refer to label)

09/08/2020 (SUPPL-69)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Drug Interactions

Newly added information:

Ibrutinib: Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib. If ibrutinib and fluconazole are concomitantly administered, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and the patient should be frequently monitored for any adverse reactions associated with ibrutinib.

Tolvaptan: Plasma exposure to tolvaptan is significantly increased (200% in AUC; 80% in Cmax) when tolvaptan, a CYP3A4 substrate, is co-administered with fluconazole, a moderate CYP3A4 inhibitor. This interaction may result in the risk of a significant increase in adverse reactions associated with tolvaptan, particularly significant diuresis, dehydration and acute renal failure. If tolvaptan and fluconazole are concomitantly administered, the tolvaptan dose should be reduced as instructed in the tolvaptan prescribing information and the patient should be frequently monitored for any adverse reactions associated with tolvaptan.

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

PATIENT INFORMATION

What To Tell Your Doctor Before You Start DIFLUCAN?

Do not take DIFLUCAN if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including:

Newly added information to bulleted line listing:

ibrutinib used for treating blood cancer
tolvaptan used to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline

02/07/2019 (SUPPL-65)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

General

(additions underlined)

…

Adrenal insufficiency has been reported in patients receiving azoles, including fluconazole.

Reversible cases of adrenal insufficiency have been reported in patients receiving fluconazole.

…

Drug Interactions:

(additions and revisions, please refer to label for more information)

Nursing Mothers

Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose, based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued breastfeeding 5 days to 19 months postpartum. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours

post-dose) was 0.39 mg/kg/day, which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis. (Labeled pediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose is 13% of 3 mg/kg/day maintenance dose). There are no data on fluconazole levels in milk after repeated use or after high-dose fluconazole. A published survey of 96 breastfeeding women who were treated with fluconazole 150 mg every other day (average of 7.3 capsules [range 1 to 29 capsules]) for lactation-associated candida of the breasts reported no serious adverse reactions in infants. Caution should be exercised when DIFLUCAN is administered to a nursing woman.

6 Adverse Reactions

Postmarketing Experience

(additions underlined)

…

Skin and Appendages: Acute generalized exanthematous pustulosis, drug eruption including fixed drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) (see WARNINGS), alopecia.

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

PATIENT INFORMATION

(additions underlined)

…

What To Tell Your Doctor Before You Start DIFLUCAN?

Do not take DIFLUCAN if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including:

…

olaparib, cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of cancer

…

What Are the Possible Side Effects of DIFLUCAN?

…

Tell your doctor or pharmacist if you experience skin rash, fever, swollen glands, increase in a type of white blood cell (eosinophilia), and inflammation of internal organs (liver, lungs, heart, kidneys, and large intestine) as they may be signs of a hypersensitivity reaction (Drug Reaction or rash with Eosinophilia and Systemic Symptoms (DRESS)).

…

Cases of reversible adrenal insufficiency have been reported with DIFLUCAN. Tell your doctor is you experience chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss or abdominal pain.

…

03/09/2018 (SUPPL-64)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Additions and/or revisions underlined:

Drug Interactions

Cisapride: … A controlled study found that concomitant treatment with fluconazole 200 mg once daily …

Pregnancy Teratogenic Effects

Potential for Fetal Harm: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.

These reported anomalies are similar to those seen in animal studies. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with DIFLUCAN 400-800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. If DIFLUCAN is used during pregnancy … informed of the potential hazard to the fetus. Spontaneous abortions and congenital abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies. There are no adequate and well-controlled studies …

Human Data

Case reports describe a distinctive and rare pattern … These effects are similar to those seen in animal studies.

Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

WARNINGS

Additions and/or revisions underlined:

(4) Potential for Fetal Harm

There are no adequate and well-controlled clinical trials of DIFLUCAN in pregnant women … These reported anomalies are similar to those seen in animal studies. If DIFLUCAN is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with DIFLUCAN 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor will discuss whether DIFLUCAN is right for you. Women who can become pregnant should think about using effective birth control while taking DIFLUCAN.

01/22/2018 (SUPPL-68)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

(Additions and/or revisions are underlined)

General

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4…Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsades de pointes.

7 Drug Interactions

(Additions and/or revisions are underlined)

…Clinically or potentially significant drug interactions between DIFLUCAN and the following agents/classes have been observed. These are described in greater detail below:

…

Hydrochlorothiazide

Alfentanil

Amiodarone

Amitriptyline, nortriptyline

…

Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg).

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

PATIENT INFORMATION

(Additions and/or revisions are underlined)

What To Tell Your Doctor Before You Start DIFLUCAN?

Do not take Diflucan if you take certain medicines. They can cause serious problems. Therefore, tell your doctor about all the medicines you take including:

…

quinidine (used to correct disturbances in heart rhythm)
amiodarone (used for treating uneven heartbeats ‘arrhythmias’)
amitriptyline or nortriptyline for depression
…