Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

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.

AFINITOR DISPERZ (NDA-203985)

(EVEROLIMUS)

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

Download Data

Expand all

02/01/2022 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Vascular: Arterial thrombotic events, lymphedema

04/16/2021 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Radiation Sensitization and Radiation Recall

New subsection added

Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment [see Adverse Reactions (6.2)].

Monitor patients closely when AFINITOR/AFINITOR DISPERZ is administered during or sequentially with radiation treatment.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Radiation Sensitization and Radiation Recall [see Warnings and Precautions (6.2)].

6.2 Postmarketing Experience

Addition of the following to the bulleted line listing:

Injury, poisoning and procedural complications: Radiation Sensitization and Radiation Recall

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Radiation Sensitization and Radiation Recall

Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment. Advise patients to inform their health care provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.12)].

…

PATIENT INFORMATION

Additions underlined

…

What are the possible side effects of AFINITOR or AFINITOR DISPERZ?

AFINITOR and AFINITOR DISPERZ can cause serious side effects.

…

Worsening side effects from radiation treatment, that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy.

…

02/13/2020 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:
5.7 Risk of Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, AFINITOR/AFINITOR DISPERZ have the potential to adversely affect wound healing.

Withhold AFINITOR/AFINITOR DISPERZ for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Risk of Impaired Wound Healing

Advise patients that AFINITOR/AFINITOR DISPERZ may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7)].

PATIENT INFORMATION

What are the possible side effects of AFINITOR AND AFINITOR DISPERZ? AFINITOR AND AFINITOR DISPERZ can cause serious side effects including:

Additions and/or revisions underlined:

risk of wound healing problems. Wounds may not heal properly during AFINITOR AND AFINITOR DISPERZ treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with AFINITOR AND AFINITOR DISPERZ.

You should stop taking AFINITOR AND AFINITOR DISPERZ at least 2 weeks before planned surgery.
Your healthcare provider should tell you when you may start taking AFINITOR AND AFINITOR DISPERZ again after surgery.

01/22/2020 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of AFINITOR/AFINITOR DISPERZ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure:

Gastrointestinal: Acute pancreatitis
Hepatobiliary: Cholecystitis and cholelithiasis
Vascular: Arterial thrombotic events
Nervous System: Reflex sympathetic dystrophy
Cardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event
Infections: Sepsis and septic shock
Blood and lymphatic disorders: Thrombotic microangiopathy

04/10/2018 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Non-infectious Pneumonitis

Addition of /AFINITOR DISPERZ to wherever the word AFINITOR is throughout the W&P section.

… Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes …

For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose.

5.2 Infections

Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP) and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients less than 6 years of age.

Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection.

Administer prophylaxis for PJP …

5.3 Severe Hypersensitivity Reactions

Newly added subsection:

Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

Additions and/or revisions underlined:

5.4 Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors

Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ … was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema.

5.5 Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR DISPERZ at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients. Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR/AFINITOR DISPERZ, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents …

5.6 Renal Failure

Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

5.9 Metabolic Disorders

Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/AFINITOR DISPERZ at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively. In non- diabetic patients, monitor fasting serum glucose prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ. For Grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity.

5.10 Myelosuppression

Newly added subsection:

Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively. Monitor complete blood count prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity.

Additions and/or revisions underlined:

5.11 Risk of Infection or Reduced Immune Response with Vaccination

The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR/AFINITOR DISPERZ. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations …

5.12 Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the clinical dose of

mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose.

6 Adverse Reactions

Addition of the following:

Severe Hypersenstivity Reactions
Stomatitis
Metabolic Disorders
Myelopsuppression

6.1 Clinical Trials Experience

This section has undergone numerous revisions in text and tables; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Gastrointestinal: Acute pancreatitis
Hepatobiliary: Cholecystitis and cholelithiasis
Vascular: Arterial thrombotic events
Nervous System: Reflex sympathetic dystrophy
Cardiac: Cardiac failure …
Infections: Sepsis and septic shock

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Effect of Other Drugs on AFINITOR/AFINITOR DISPERZ

Inhibitors

Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors.

Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended.

Inducers

Increase the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended.

7.2 Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors

Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily. Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Data

Animal Data

… Embryo-fetal toxicities in rats occurred at doses greater than or equal to 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on body surface area. The effect in rabbits occurred …

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production.

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to starting AFINITOR/AFINITOR DISPERZ.

Contraception

AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to pregnant women. Females: Advise female patients of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose.

Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose.

Infertility

Females: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR/AFINITOR DISPERZ. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in female patients.

Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in male patients

8.4 Pediatric Use

Additions and/or revisions underlined:

TSC-Associated SEGA

The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of AFINITOR/AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo- controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients. The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA.

In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients less than 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients less than 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients greater than or equal to 6 years. Thirty-five percent of 23 AFINITOR-treated patients less than 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients greater than or equal to 6 years.

TSC-Associated Partial-Onset Seizures

The safety and effectiveness of AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients. The safety and effectiveness of AFINITOR DISPERZ and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures.

The incidence of infections and serious infections were reported at a higher frequency in patients less than 6 years of age compared to patients greater than or equal to 6 years old. Seventy-seven percent of 70 AFINITOR DISPERZ-treated patients less than 6 years had at least one infection, compared to 53% of 177 AFINITOR DISPERZ-treated patients greater than or equal to 6 years. Sixteen percent of 70 AFINITOR DISPERZ-treated patients less than 6 years of age had at least 1 serious infection, compared to 4% of 177 AFINITOR DISPERZ-treated patients greater than or equal to 6 years of age. Two fatal cases due to infections were reported in pediatric patients.

Other Indications

The safety and effectiveness of AFINITOR/AFINITOR DISPERZ in pediatric patients have not been established in:

Hormone receptor-positive, HER2-negative breast cancer
Neuroendocrine tumors (NET)
Renal cell carcinoma (RCC)
TSC-associated renal angiomyolipoma

8.6 Hepatic Impairment

Additions and/or revisions underlined:

AFINITOR/AFINITOR DISPERZ exposure may increase in patients with hepatic impairment.

For patients with breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the AFINITOR dose as recommended.

For patients with TSC-associated SEGA and TSC-associated partial-onset seizures who have severe hepatic impairment (Child-Pugh C), reduce the starting dose of AFINITOR/AFINITOR DISPERZ as recommended and adjust the dose based on everolimus trough concentrations.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Non-infectious Pneumonitis

Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider.

Infections

Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider.

Hypersensitivity Reactions

Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness.

Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors

Advise patients to avoid angiotensin-converting enzyme (ACE) inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema.

Renal Impairment

Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment.

Impaired Wound Healing

Advise patients of the risk of impaired wound healing or dehiscence during treatment.

Geriatric Patients

Inform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients greater than or equal to 65 years compared to patients less than 65 years.

Metabolic Disorders

Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy

Myelosuppression

Advise patients of the risk of myelosuppression and the need to monitor complete blood counts periodically during therapy.

Risk of Infection or Reduced Immune Response with Vaccination

Advise patients to avoid the use of live vaccines …

PATIENT INFORMATION

Section revised; please see label for complete information.