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.

ORAVIG (NDA-022404)

(MICONAZOLE)

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

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02/04/2020 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety of ORAVIG was assessed in 480 adult subjects: 315 HIV-infected subjects, 147 subjects with head and neck cancer, and 18 healthy subjects.

HIV Infected Patients

Two trials were conducted in immunocompromised HIV-infected patients: one randomized, double-blind, double-dummy, active-controlled design (N = 290 ORAVIG, 287 control) and one non-comparative trial (N = 25).

In the randomized, double blind trial (Study 1), 290 HIV infected subjects used ORAVIG once daily for 14 days, and 287 subjects used 10 mg clotrimazole troches five times daily for 14 days. Adverse reactions occurring in greater than or equal to 2% of patients in either treatment are presented in Table 1.

Table 1 Adverse Reactions (Treatment-Emergent) Occurring in greater than or equal to 2% of HIV- Infected Patients in the Controlled Clinical Trial

…

Overall local adverse reactions, including oral discomfort, oral burning, oral pain, gingival pain, gingival swelling, gingival pruritis, tongue ulceration, mouth ulceration, glossodynia, dry mouth, application site pain or discomfort, toothache, loss of taste, and altered taste, were reported by 35 (12.1%) patients who received miconazole buccal tablet compared to 27 (9.4%) patients who received clotrimazole troches.

Head and Neck Cancer Patients

In the randomized, open-label comparative trial of oropharyngeal candidiasis in patients with head and neck cancer who had received radiation therapy (Study 2), 147 patients used ORAVIG once daily for 14 days and 147 patients used 125 mg of miconazole oral gel four times daily for 14 days. Adverse reactions occurring in greater than or equal to 2% of patients in either arm are listed in Table 2.

Table 2: Adverse Reactions (Treatment-Emergent) Occurring in greater than or equal to 2% of Patients with Head and Neck Cancer who had Received Radiation Therapy (Controlled Clinical Trial)

…

Overall local adverse reactions, including oral discomfort, oral pain, dry mouth, glossodynia, loss of taste, altered taste, tongue ulceration, mouth ulceration, tooth disorder, and application site discomfort or pain, were experienced by 14 (9.5%) patients who used ORAVIG compared to 16 (10.9%) patients who used miconazole gel.

Overall ORAVIG Safety Experience In Patients and Healthy Subjects

Adverse reactions reported in the overall safety database of 480 subjects who received miconazole buccal tablet is listed in Table 3.

Table 3 Adverse Reactions Reported in greater than or equal to 2% of Patients and Healthy Subjects who Received ORAVIG in Clinical Trials

…

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on findings from animal data, ORAVIG may cause fetal harm when administered to pregnant women. There are no available data on ORAVIG use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, prolonged gestation, dystocia and/or increased number of resorptions were observed after oral administration of miconazole nitrate during organogenesis to pregnant rats and rabbits. Advise pregnant women of the potential risk to a fetus.

The 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 US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data:

Miconazole nitrate administered orally at doses of 80 mg/kg/day or higher to pregnant rats or rabbits crossed the placenta and resulted in embryo- and fetotoxicity, including increased fetal resorptions. These doses also resulted in prolonged gestation and dystocia in rats, but not in rabbits. Embryofetotoxicity was not observed in intravenous studies with miconazole at lower doses of 40 mg/kg/day in rats and 20 mg/kg/day in rabbits, which are approximately 8 times higher than the dose a patient would receive if she swallowed an ORAVIG buccal tablet, based on body surface area comparisons. Teratogenicity was not reported in any animal study with miconazole.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no available information on the presence of miconazole in human milk, or the effects on the breastfed child, or the effects on milk production following use of ORAVIG.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORAVIG and any potential adverse effects on the breastfed infant from ORAVIG or from the underlying maternal condition.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Important Administration Instructions

The tablet should be used immediately after removal from the bottle.

Instruct patients not to crush, chew, or swallow the tablet.

The rounded side of the tablet should be applied to the upper gum above the incisor tooth in the morning, after brushing the teeth.
The tablet should be held in place for 30 seconds with a slight pressure of the finger over the upper lip to make the tablet stick to the gum.
The tablet may be used if it sticks to the cheek, inside of the lip or the gum.
If the tablet does not adhere, it should be repositioned.
As the ORAVIG tablet absorbs moisture from the mouth, it will slowly dissolve over time and should be left in place – there is no need to remove the tablet.
Subsequent applications of ORAVIG should be made to alternate sides of the gum.
If ORAVIG does not stick or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet does not adhere, a new tablet should be placed.
If ORAVIG is swallowed within the first 6 hours, the patient should drink a glass of water and a new tablet should be applied only once.

If ORAVIG falls off or is swallowed after it was in place for 6 hours or more, a new tablet should not be applied until the next regularly scheduled dose.

Patients should avoid situations that could interfere with the sticking of the tablet including:

touching or pressing the tablet after placement
wearing upper denture
chewing gum
hitting tablet when brushing teeth

rinsing mouth too vigorously

Hypersensitivity and Other Adverse Reactions

Patients who develop hives, skin rash, or other symptoms of an allergic reaction, and patients who develop swelling or pain, at the tablet application site should stop ORAVIG and contact a healthcare provider. Patients may experience other adverse reactions including diarrhea, headache, nausea, and change in taste.

Potential Embryo-fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

PATIENT INFORMATION

(Extensive changes; please refer to label)