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.

STENDRA (NDA-202276)

(AVANAFIL)

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

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10/18/2022 (SUPPL-20)

Approved Drug Label (PDF)

4 Contraindications

4.3 Concomitant Guanylate Cyclase (GC) Stimulators

Additions and/or revisions underlined:

Do not use STENDRA in patients who are using a GC stimulator, such as riociguat or vericiguat. PDE5 inhibitors, including STENDRA may potentiate the hypotensive effects of GC stimulators.

5 Warnings and Precautions

5.4 Effects on Eye

Additions and/or revisions underlined:

…

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials for STENDRA. and therefore, until further information is available, STENDRA is not recommended for use in these patients.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of STENDRA. 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. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

Cardiovascular and cerebrovascular:

Serious cardiovascular and cerebrovascular events, including myocardial infarction, sudden cardiac death, cerebrovascular accident, and subarachnoid hemorrhage, have been reported post-marketing in temporal association with the use of STENDRA. All of these patients had preexisting cardiovascular risk factors. The occurrence of sexual activity was not stated in the majority of reports, although events were reported to occur both with and without sexual activity. It is not possible to determine whether these events are related directly to STENDRA, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions (5.1) and Patient Counseling Information (17.2)].

Nervous: transient global amnesia

Special senses:

Ophthalmologic: vitreous detachment, visual impairment

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, such as STENDRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [see Warnings and Precautions (5.4)].

Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, such as STENDRA. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of PDE5 inhibitors such as STENDRA, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions (5.5) and Patient Counseling Information (17.6)].

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).

…

Physicians should discuss with patients the contraindication of STENDRA with use of guanylate cyclase stimulators such as riociguat or vericiguat.

PATIENT INFORMATION

Extensive changes/revisions; please refer to label

08/03/2018 (SUPPL-18)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

STENDRA is not indicated for use in females.

There are no data with the use of STENDRA in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of avanafil during organogenesis at exposures for total avanafil at approximately 8 and 6 times, respectively, the Maximum Recommended Human Dose (MRHD) of 200 mg based on AUC.

Data

Animal Data

In pregnant rats administered orally at 100, 300, or 1000 mg/kg/day from gestation days 6 to 17, no evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed at up to 300 mg/kg/day. This dose is equivalent to exposures … At the maternally toxic dose (1000 mg/kg/day), decreased fetal body weight occurred with no signs of teratogenicity. In pregnant rabbits administered orally at 30, 60, 120, or 240 mg/kg/day from gestation days 6 to 18, no teratogenicity was observed at exposures up to approximately 6 times the human exposure at the MRHD based on AUCs for total avanafil.

In a pre- and post-natal development study in rats given orally at 100, 300, or 600 mg/kg/day on … equal to 17 times the human exposure to total avanafil at the MRHD. There was no effect on reproductive … The no observed adverse effect level (NOAEL) for developmental toxicity (100 mg/kg/day) was observed at exposures to total avanafil approximately 2-fold greater than the systemic exposure in humans at the MRHD.

8.2 Lactation

PLLR conversion; additions underlined:

Risk Summary

STENDRA is not indicated for use in females.

There is no information on the presence of avanafil and/or its metabolites in human or animal milk, the effects on the breastfed child, or the effects on milk production.

8.3 Females and Males of Reproductive Potential

PLLR conversion; additions underlined:

Infertility

There have been no studies evaluating the effect of STENDRA on fertility in men.

Based on studies in animals, decreased fertility, abnormal sperm motility and morphology, and altered estrous cycles were observed in rats. The abnormal sperm findings were reversible at the end of a 9-week drug-free period.

08/16/2017 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Effects on the Eye

Addition of the following:

… greater than or equal to 50 …

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION.

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

PATIENT INFORMATION

How should I take STENDRA?

Additions and/or revisions underlined:

Take STENDRA 50 mg as early as approximately 30 minutes before sexual activity.
STENDRA may uncommonly cause:

sudden vision loss in 1 or both eyes. Sudden vision loss in 1 or both eyes can be a sign of a serious eye problem called non-arteritic anterior ischemic optic neuropathy (NAION). It is uncertain whether PDE5 inhibitors directly cause vision loss. Stop taking STENDRA and call your healthcare provider right away …
General information about the safe and effective use of STENDRA.
For more information, go to www.STENDRA.com or call 1-844-458-4887.