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.

LEVITRA (NDA-021400)

(VARDENAFIL HYDROCHLORIDE)

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

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03/15/2023 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Potential for Drug Interactions with Strong or Moderate CYP3A4 Inhibitors

Section title revised

Additions and/or revisions underlined:

Concomitant administration with strong CYP3A4 inhibitors (such as ritonavir, indinavir, cobicistat, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil.

…

7 Drug Interactions

7.2 Effect of Other Drugs on Vardenafil

Additions and/or revisions underlined:

…

Strong CYP3A4 inhibitors

…

Ritonavir (600 mg b.i.d.) co-administered with LEVITRA 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13- fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly strong CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg LEVITRA dose in a 72-hour period when used in combination with ritonavir. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2)].

Cobicistat with LEVITRA can result in increased plasma concentrations, therefore it is recommended that a single 2.5 mg dose of LEVITRA should not be exceeded in a 72-hour period. [See Dosage and Administration (2.4) and Warnings and Precautions (5).]

…

7.3 Effects of Vardenafil on Other Drugs

Additions and/or revisions underlined:

…

In vitro data suggest that vardenafil has the potential to inhibit P-glycoprotein (P-gp) at therapeutic doses. While concomitant use of LEVITRA did not significantly increase plasma concentrations of digoxin, a P-gp substrate, the effect on plasma concentrations of P-gp substrates that are more sensitive than digoxin (e.g. dabigatran) is not known.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

LEVITRA is not indicated for use in females.

There are no data with the use of LEVITRA in pregnant women to inform any drug-associated risks. In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of vardenafil during organogenesis at exposures for unbound vardenafil and its major metabolite at approximately 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg based on AUC(see Data).

Data

Animal Data

…

8.2 Lactation

Section title revised

Additions and/or revisions underlined:

Risk Summary

LEVITRA is not indicated for use in females.

There is no information on the presence of vardenafil and its major metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. Vardenafil is present in rat milk of lactating rats (see Data).

Data

Vardenafil was secreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma. Following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

…

CAN OTHER MEDICATIONS AFFECT LEVITRA?

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. LEVITRA and other medicines may affect each other. Always check with your doctor before starting or stopping any medicines. Especially tell your doctor if you take any of the following:

Medicines called nitrates (see “What important information should you know about LEVITRA?”).
Ketoconazole or itraconazole (such as Nizoral® or Sporanox®).
Ritonavir (Norvir®) or indinavir sulfate (Crixivan®) saquinavir (Fortavase® or Invirase®) or atazanavir (Reyataz®) or cobicistat.

...

GENERAL INFORMATION ABOUT LEVITRA

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use LEVITRA for a condition for which it was not prescribed. Do not give LEVITRA to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about LEVITRA. If you would like more information, talk with your healthcare provider. You can ask your doctor or pharmacist for information about LEVITRA that is written for health professionals.

For more information you can also visit www.LEVITRA.com, or call 1-888-825-5249.

…

08/16/2017 (SUPPL-20)

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 INFOMATION

Additions and/or revisions underlined:

WHAT ARE THE POSSIBLE SIDE EFFECTS OF LEVITRA?

LEVITRA may uncommonly cause:

… In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including vardenafil) reported a sudden decrease or loss of vision in one or both eyes. It is uncertain whether PDE5 inhibitors directly cause the vision loss. If you experience sudden decrease or loss of vision …