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.

DIFICID (NDA-201699)

(FIDAXOMICIN)

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

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01/24/2020 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Not for Use in Infections Other than C. difficile-Associated Diarrhea

(Newly added subsection)

DIFICID is not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin. DIFICID has not been studied for the treatment of infections other than CDAD. DIFICID should only be used for the treatment of CDAD.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Adults

The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 adult patients with CDAD in two active-controlled trials with 86.7% of patients receiving a full course of treatment.

Thirty-three adult patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the DIFICID and vancomycin patients in Phase 3 trials. The most common selected adverse reactions occurring in greater than or equal to 2% of adult patients treated with DIFICID are listed in Table 2.

Pediatrics

The safety of DIFICID in pediatric patients 6 months to less than 18 years of age was evaluated in a Phase 2 single-arm trial in 38 patients and a Phase 3 randomized, active-controlled trial in 98 patients treated with DIFICID and 44 patients treated with vancomycin. In both studies, patients received DIFICID orally twice daily for 10 days. Patients <2 years of age, or weighing <12.5 kg, or unable to swallow tablets received weight-based doses of DIFICID oral suspension. Patients weighing at least 12.5 kg and able to swallow tablets received the 200 mg DIFICID tablet. The age range in the Phase 2 trial was 11 months to 17 years and in the Phase 3 trial was 1 month to 17 years (one patient was less than 6 months of age).

One death occurred in the Phase 2 single-arm trial. In the Phase 3 trial, there were 3 deaths in DIFICID-treated patients and no deaths in vancomycin-treated patients during the study period (40 days). All deaths occurred in patients less than 2 years of age and appeared to be related to underlying comorbidities.

Treatment discontinuation due to adverse reactions occurred in 7.9% (3/38) of patients in the Phase 2 trial, and in 1% (1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients, respectively, in the Phase 3 trial. The most common selected adverse reactions occurring in greater than or equal to 5% of pediatric patients treated with DIFICID in the Phase 3 trial are listed in Table 3.

The following adverse reactions were reported in <5% of pediatric patients taking DIFICID in clinical trials:

Skin and Subcutaneous Tissue Disorders: urticaria, pruritus

6.2 Post Marketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of DIFICID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions (dyspnea, angioedema, rash, pruritus)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of DIFICID for the treatment of CDAD have been established in pediatric patients 6 months to less than 18 years of age. Use of DIFICID in these age groups is supported by evidence from adequate and well-controlled trials of DIFICID in adults with CDAD and pharmacokinetic, safety and efficacy data from pediatric trials. No new safety signals associated with the use of DIFICID in pediatric patients were identified in the pediatric trials.

The safety and effectiveness of DIFICID have not been established in pediatric patients younger than 6 months of age.

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

Patient Information

(Extensive changes; please refer to label)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Oral Suspension

Remove the bottle from the refrigerator 15 minutes prior to each administration.

Instruct patients or caregivers to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform patients or caregivers that oral dosing syringes may be obtained from their pharmacy.

Inform the patients or caregivers that DIFICID oral suspension should be prepared by a healthcare professional. Advise them to contact a healthcare professional for any questions regarding administration of DIFICID oral suspension.

Administration with Food

Inform patients and caregivers that DIFICID tablets and oral suspension may be taken with or without food.

04/05/2019 (SUPPL-11)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

(addition underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

…

PATIENT INFORMATION

(addition of a newly developed US proposed patient labeling (USPPI) , please refer to label)

03/15/2019 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID.

5 Warnings and Precautions

5.1 Lack of Effectiveness for Infections other than C. difficile-Associated Diarrhea

(Additions and/or revisions are underlined)

DIFICID should only be used for the treatment of C. difficile-associated diarrhea. DIFICID is not effective for treatment of other types of infections due to minimal systemic absorption of fidaxomicin.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

The limited available data on use of DIFICID in pregnant women are insufficient to inform any drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Embryo-fetal reproduction studies in rats and rabbits dosed intravenously during organogenesis revealed no evidence of harm to the fetus at fidaxomicin and OP-1118 (its main metabolite) exposures 65-fold or higher than the clinical exposure at the DIFICID recommended dose.

The estimated background risk of major birth defects and miscarriage for the indicated populations 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 Data

In pregnant rats, fidaxomicin was administered intravenously at doses of 4, 8, and 15 mg/kg/day from gestation day 6 through 17 (during the period of organogenesis). No embryo/fetal effects were noted in this study at exposures (AUC) 193-fold higher for fidaxomicin, and 65-fold higher for OP-1118 than the clinical exposure at the DIFICID recommended dose.

In pregnant rabbits, fidaxomicin was administered intravenously at doses of 2, 4, and 7.5 mg/kg/day from gestation day 6 through 18 (during the period of organogenesis). No embryo/fetal effects were noted in this study at exposures 66-fold higher for fidaxomicin, and 245-fold higher for OP-1118 than the clinical exposure at the DIFICID recommended dose.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There is no information on the presence of fidaxomicin or its main metabolite, OP-1118, in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DIFICID and any potential adverse effects on the breastfed infant from DIFICID or from the underlying maternal condition.