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.

APTIVUS (NDA-022292)

(TIPRANAVIR)

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

Download Data

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06/18/2020 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

(Table updated)

7 Drug Interactions

(Extensive changes; please refer to label)

06/22/2018 (SUPPL-10)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; as below:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to APTIVUS 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 and an Expanded Access program are not sufficient to adequately assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Tipranavir use during pregnancy has been evaluated in a limited number of women as reported by the APR and an Expanded Access program, and available data show no birth defects in 13 first trimester exposures compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.

In animal reproduction studies, fetal toxicities were observed with tipranavir at maternally toxic doses with systemic exposures (AUC) less than those in humans at the recommended human dose (RHD).

Data

Human Data

Based on prospective reports to the APR and an Expanded Access program for approximately 17 live births following exposure to tipranavir-containing regimens (including 13 live births exposed in the first trimester and 4 live births exposed in the second/third trimester), there were no birth defects reported in live-born infants.

Tipranavir has been shown to cross the placenta.

Animal Data

Tipranavir was administered orally to pregnant rats (at 0, 40, 400, or 1000 mg/kg/day from gestation day 6 to 17) and rabbits (at 0, 75, 150, or 375 mg/kg/day from gestation day 6 to 20). In rats, fetal toxicities including decreased body weight and sternebrae ossification occurred at maternally toxic doses (greater than or equal to 400 mg/kg/day) (approximately 0.8 times human exposure at the RHD). In rabbits, fetal toxicities including decreased fetal body weights, wavy ribs, and bent femurs occurred at a maternally toxic dose (375 mg/kg/day) (approximately 0.05 times human exposure at the RHD). Maternal toxicity included an increased incidence of abortions at doses greater than or equal to 150 mg/kg/day (approximately 0.05 times human exposure at the RHD).

In the pre/post-natal development study, tipranavir was administered orally to rats at 0, 40, 400, 1000 mg/kg/day from gestation day 6 to lactation day 21. The only significant effect observed was growth inhibition of the offspring at maternally toxic doses (greater than or equal to 400 mg/kg/day) (approximately 0.8 times human exposure at the RHD).

8.2 Lactation

PLLR conversion; as below:

Risk Summary

he Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breast-feed their infants to avoid risking postnatal transmission of HIV-1 infection. There is no information regarding the presence of tipranavir in human milk, the effects on the breastfed infant, or the effects on milk production. Tipranavir is present in rat milk (see Data). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive patients), and (3) any possible adverse effects of APTIVUS, mothers should not breastfeed if they are receiving APTIVUS.

Data

In a lactation study, tipranavir was excreted into the milk of lactating rats following a single oral dose of tipranavir (10 mg/kg) on lactation/postpartum day 14, with a maximal milk concentration achieved 2 hours post-administration (milk concentration 0.13 times that of maternal plasma concentration).

8.3 Females and Males of Reproductive Potential

PLLR conversion; as below:

Contraception

Use of APTIVUS may reduce the efficacy of estrogen-based oral contraceptives. Advise patients to use alternative methods of nonhormonal contraception.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Administration
- Instruct patients to swallow APTIVUS capsules whole. They must not be opened or chewed.
Pregnancy Registry
- Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to APTIVUS during pregnancy.
Lactation
- Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.

09/15/2016 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

4.2 Drug Interactions (addition underlined)

Table 1: Drugs within Class that are Contraindicated with APTIVUS Co-administered with Ritonavir

Drug Class: Antipsychotics- Lurasidone

Clinical Comments: Potential for serious and/or life-threatening reactions.

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

4.2 Drug Interactions (addition underlined)

Who should not take APTIVUS?

Do not take APTIVUS if you:

• take any of the following types of medicines because you could have serious side effects:

o Latuda® (lurasidone)