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.

REVATIO (NDA-021845)

(SILDENAFIL CITRATE)

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

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01/31/2023 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Visual Loss

Additions and/or revisions underlined:

When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported post marketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio (“crowded disc”).

Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking REVATIO.

There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of REVATIO in patients with retinitis pigmentosa is not recommended.

5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease

Subsection title revised
Additions and/or revisions underlined:

In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received REVATIO than by those randomized to placebo. The effectiveness and safety of REVATIO in the treatment of PH secondary to sickle cell disease has not been established.

6 Adverse Reactions

Additions and/or revisions underlined:

…

Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

7 Drug Interactions

Additions and/or revisions underlined:

Nitrates

Concomitant use of REVATIO with nitrates in any form is contraindicated [see Contraindications (4)].

Strong CYP3A Inhibitors

Concomitant use of REVATIO with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)].

Moderate-to-Strong CYP3A Inducers

Concomitant use of REVATIO with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of REVATIO may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of REVATIO to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and efficacy of REVATIO have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise Use of REVATIO for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of REVATIO have not been established in pediatric patients younger than 1 year of age.

During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg three times a day.

…

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of REVATIO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

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 and Instructions for Use).

…

PATIENT INFORMATION

Extensive changes; please refer to label for complete information

02/01/2018 (SUPPL-18)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (See Data).

The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.

Data

Animal Data

No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the

no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis).

8.2 Lactation

(PLLR conversion)

Risk Summary

Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of REVATIO to an infant during lactation.

07/31/2017 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Visual Loss

Additions and/or revisions underlined:

… underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 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 PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION. Advise patients to seek immediate medical attention in the event of a sudden loss of vision …

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following:

Ophthalmologic

NAION