Get Email Alerts |
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.
SPORANOX (NDA-020083)
(ITRACONAZOLE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/05/2024 (SUPPL-68)
Boxed Warning
…
Drug Interactions:
Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®. Some examples of drugs that are contraindicated for coadministration with SPORANOX® Capsules are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
…
5 Warnings and Precautions
PRECAUTIONSAdditions and/or revisions underlined:
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 1 time the maximum recommended human dose [MRHD] of 400 mg/day based on body surface area comparisons). Male rats treated with 25 mg/kg/day (0.6 times the MRHD based on body surface area comparisons) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (1.2 times the MRHD based on body surface area comparisons) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.
Itraconazole produced
no mutagenic effects
when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella
typhimurium (6 strains)
and Escherichia coli, in the mouse
lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes,
in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts
cells, in a dominant lethal mutation test in male and female mice, and in
micronucleus tests in mice and rats.
Itraconazole did not affect the fertility of male or female rats treated orally
with dosage levels of up to 40 mg/kg/day
(1 time the MRHD based
on body surface area comparisons), even though parental toxicity
was present at this dosage level. More severe signs of parental
toxicity, including death,
were present in the next higher dosage
level, 160 mg/kg/day (4 times the
MRHD based on body surface area comparisons).
7 Drug Interactions
Changes to table 1; please refer to label for complete information
Additions and/or revisions underlined:
Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®. Some examples of drugs for which plasma concentrations increase are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Some specific examples are listed in PRECAUTIONS: Drug Interactions.
…
8 Use in Specific Populations
Additions and/or revisions underlined:
Pregnancy: Teratogenic Effects:
Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40-160 mg/kg/day (1-4 times the MRHD based on body surface area comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has been shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.
…
Pediatric Use:
The efficacy and safety of SPORANOX® have not been established in pediatric patients.
The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day
(0.5 times the MRHD of 400 mg based on body surface area comparisons). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (2 times the MRHD based on body surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on body surface area comparisons) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.
10/19/2023 (SUPPL-67)
Boxed Warning
Additions and revisions underlined:
Coadministration of the following drugs are contraindicated with SPORANOX® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
4 Contraindications
Additions and revisions underlined:
Drug Interactions:
Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®. Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
5 Warnings and Precautions
PrecautionsAddition of the following to the Drug Interactions table: finerenone, voclosporin, mobocertinib, entrectinib, and pemigatinib
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling InformationAdditions and revisions underlined:
Serious medical problems that affect the heart and
other parts of your body can happen if you take SPORANOX with certain other medicines. Do not take
SPORANOX if you also take the following medicines:
. . .
finerenone
voclosporin
. . .
The most common side effects of SPORANOX include: headache, rash, digestive system problems (such as nausea and vomiting), and edema.
12/05/2022 (SUPPL-65)
Boxed Warning
Additions and/or revisions underlined:
…
Coadministration with venetoclax is contraindicated in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose initiation and ramp-up phase of venetoclax.
…
4 Contraindications
Additions and/or revisions underlined:
…
Drug Interactions:
…
Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome.
…
5 Warnings and Precautions
PRECAUTIONS
…
Drug Interactions:
…
Table 1 Drug Interactions with SPORANOX® that Affect Concomitant Drug Concentrations
Additions and/or revisions; please refer to label to view Table 1.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions and/or revisions underlined:
…
What is the most important information I should know about SPORANOX?
…
2. Heart problems and other serious medical problems. Serious medical problems that affect the heart and other parts of your body can happen if you take SPORANOX with certain other medicines. Do not take SPORANOX if you also take the following medicines:
…
venetoclax (see below)
Do not take SPORANOX with venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma when you first start treatment with venetoclax or with increasing doses of venetoclax.
…
03/08/2019 (SUPPL-63)
5 Warnings and Precautions
PRECAUTIONSDrug Interactions:
Effect of SPORANOX® on Other Drugs
(addition underlined)
…
*CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.
…
8 Use in Specific Populations
Pregnancy:Teratogenic effects:
(addition underlined)
… Highly effective contraception should be continued throughout SPORANOX® therapy and for 2 months following the end of treatment.
...
05/08/2018 (SUPPL-62)
5 Warnings and Precautions
PRECAUTIONSAddition of the following:
Immunocompromised Patients:
In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of SPORANOX® capsules may be decreased. Therefore, the dose should be adjusted based on the clinical response in these patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONSignificant revisions to the content and format; please refer to label for complete information.
10/07/2017 (SUPPL-61)
Boxed Warning
Additions and/or revisions underlined:
Drug Interactions: Coadministration of the following drugs are contraindicated with SPORANOX® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
4 Contraindications
Drug InteractionsAdditions and/or revisions underlined:
Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX®. Plasma concentrations increase for the following drugs: levaceytlmethadol (levomethadyl), methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
5 Warnings and Precautions
PRECAUTIONSDrug Interactions:
Additions and/or revisions underlined:
Effect of SPORANOX® on Other Drugs
Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, SPORANOX® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions
associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX®.
Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX®.
Table 1 Drug Interactions with SPORANOX® that Affect Concomitant Drug Concentrations New table labeled as Table 1 with new information; please refer to label for complete information.
Effect of Other Drugs on SPORANOX®
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Some concomitant drugs have the potential to interact with SPORANOX® resulting in either increased or sometimes decreased concentrations of SPORANOX®. Increased concentrations may increase the risk of adverse reactions associated with SPORANOX®.
Decreased concentrations may reduce SPORANOX® efficacy.
Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX®.
Table 2. Drug Interactions with Other Drugs that Affect SPORANOX Concentrations Newly added table; please refer to label for complete information.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions and/or revisions underlined:
WHO SHOULD NOT TAKE SPORANOX®?
Never take SPORANOX® if you:
are taking any of the medicines listed below. Dangerous or even life-threatening side effects could result:
avanafil (such as Stendra™)
eliglustat (such as Cerdelga™) [if you know you do not break down drugs that are broken down by the enzyme CYP 2D6]
isavuconazole (such as Cresemba®)
lomitapide (such as Juxtapid™)
naloxegol (such as Movantik®)
03/17/2017 (SUPPL-60)
Boxed Warning
(Additions and/or revisions are underlined)
Drug Interactions: Coadministration of the following drugs are contraindicated with SPORANOX Capsules: … nisoldipine, ivabradine, ranolazine,…
4 Contraindications
(Additions and/or revisions are underlined)
Drug Interactions: …Plasma concentrations increase for the following drugs: nisoldipine, ivabradine, ranolazine,…
7 Drug Interactions
Table 1: Drugs that may have their plasma concentrations increased by itraconazole (Table has been revised; please refer to label)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(Additions and/or revisions are underlined)
WHO SHOULD NOT TAKE SPORANOX?
Never take SPORANOX if you:
are taking any of the medicines listed below. Dangerous or even life-threatening side effects could result:
ivabradine (such as Corlanor)