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.

FUZEON (NDA-021481)

(ENFUVIRTIDE)

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

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12/27/2018 (SUPPL-32)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

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

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to FUZEON during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263 .

Risk Summary

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or fetal outcomes. Limited number of reports on the use of enfuvirtide during pregnancy has been submitted to the APR and the number of exposures to enfuvirtide is insufficient to make a risk assessment compared to a reference population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the U.S. general population is 15–20%.

In animal reproduction studies, no adverse developmental effects were observed with subcutaneous administration of enfuvirtide at exposures greater than or equal to approximately 2 times higher than human exposure at the recommended human dose (RHD) based on surface area.

Data

Animal Data

In the embryofetal development studies, enfuvirtide was administered by subcutaneous injection to pregnant rats at doses up to 500 mg/kg/day from gestation days 6 to 17, and to pregnant rabbits at doses up to 30 mg/kg/day from gestation days 6 to 18. No embryofetal toxicities were observed at doses up to the highest doses tested (27 times and 3.2 times higher than human exposure at the RHD in rats and rabbits, respectively, based on surface area).

In the pre/postnatal development study, enfuvirtide was administered by subcutaneous injection to pregnant rats at doses up to 30 mg/kg/day from gestation day 6 to postnatal day 20. No toxicities were observed at doses up to 30 mg/kg/day (1.6 times higher than human exposure at the RHD based on surface area).

8.2 Lactation

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

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV-1 infected mothers not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1.

There are no human data available regarding the presence of enfuvirtide or its metabolites (amino acids and peptide fragments) in human milk, the effects on the breastfed infant, or the effects on milk production. When enfuvirtide was administered to lactating rats, enfuvirtide was likely present in the milk.

Because of both the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV- positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breast- feed if they are receiving FUZEON.

Data

In a lactation study at doses of 200 mg/kg, very low levels of enfuvirtide or enfuvirtide metabolites (amino acids and peptide fragments) were excreted in milk following subcutaneous administration to lactating rats up to 48 hours post-dose on post- partum/lactation days 14 and 18.

8.4 Pediatric Use

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

Use of FUZEON in pediatric patients weighing at least 11kg is supported by evidence from adequate and well-controlled studies of FUZEON in adult and by two pediatric studies evaluating the safety, pharmacokinetics and efficacy of FUZEON in subjects 6 years of age and older:

was an open-label, multicenter trial that evaluated the safety and antiviral activity of FUZEON in 11, treatment-experienced pediatric subjects 6 to 12 years (median age of 9 years).
T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in 52, treatment-experienced pediatric subjects 5 years and older (median age of 12 years).
Overall, the adverse experiences, including ISRs in the 63 pediatric subjects were similar to those observed in adult subjects, although infections at site of injection (cellulitis or abscess) were more frequent in adolescents than in adults, with 4 events occurring in 3 of 28 (11%) subjects.

8.6 Hepatic Impairment

(Additions and/or revisions are underlined)

No dosage adjustments of FUZEON are needed in patients with hepatic impairment.

8.7 Renal Impairment

(Additions and/or revisions are underlined)

No dosage adjustments of FUZEON are needed in patients with renal impairment.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Administration with Biojector® 2000

Inform patients that nerve pain (neuralgia and/or paresthesia) associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON.

Post-injection Bleeding

Advise patients about the risk of post-injection bleeding if they are receiving anticoagulants or have coagulation disorders such as hemophilia.

Systemic Hypersensitivity

Advise patients of the possibility of a systemic hypersensitivity reaction to FUZEON. Advise patients to discontinue therapy and immediately seek medical evaluation if they develop signs/symptoms of systemic hypersensitivity such as combinations of rash, fever, nausea and vomiting, chills, rigors, and/or hypotension.

Pneumonia

Advise patients that an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in clinical trials. Advise patients to seek medical evaluation immediately if they develop signs or symptoms suggestive of pneumonia (cough with fever, rapid breathing, shortness of breath).

Pregnancy Exposure Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FUZEON during pregnancy.

Lactation

Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

Important Dosing and Administration Instructions

Inform patients that FUZEON must be taken as part of a combination antiretroviral regimen and that use of FUZEON alone may lead to rapid development of virus resistant to FUZEON and possibly other agents of the same class.
Instruct patients and caregivers in the use of aseptic technique when administering FUZEON in order to avoid injection site infections. Appropriate training for FUZEON reconstitution and self-injection must be given by a healthcare provider, including a careful review of the FUZEON Patient Package Insert and FUZEON Injection Instructions. The first injection should be performed under the supervision of an appropriately qualified healthcare provider. It is recommended that the patient and/or caregiver’s understanding and use of aseptic injection techniques and procedures be periodically re-evaluated.
Instruct patients and caregivers on the preferred anatomical sites for administration (upper arm, abdomen, anterior thigh). FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial sections of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites.
Instruct patients and caregivers in the proper techniques for preparation, injection and disposal of needles and syringes (including not recapping needles) in order to avoid needle stick injuries. Advise patients not to reuse needles or syringes and of safe disposal procedures, including the use of a puncture-resistant container, for disposal of used needles and syringes. Instruct patients on the safe disposal of full containers as per local requirements. Caregivers who experience an accidental needle stick after patient injection should contact a healthcare provider immediately.
Inform patients to contact their healthcare provider for any questions regarding the administration of FUZEON.
Inform patients not to change the dose or dosing schedule of FUZEON or any antiretroviral medication without consulting their healthcare provider.
Inform patients to contact their healthcare provider immediately if they stop taking FUZEON or any other drug in their antiretroviral regimen.

Inform patients that they can obtain more information on the self-administration of FUZEON at www.FUZEON.com or by calling 1-877-4-FUZEON (1-877-438-9366 ).

….

Other

Patient Information

(Section format has been revised, please refer to label.)

FUZEON(enfuvirtide) Injection Instructions

(New section added, please refer to the label)