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.

ZORTRESS (NDA-021560)

(EVEROLIMUS)

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

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09/14/2023 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.22 Cannabidiol Drug Interactions

Newly added subsection:

When cannabidiol and Zortress are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of Zortress should be considered as needed when Zortress is coadministered with cannabidiol [see Dosage and Administration (2.3), Drug Interactions (7.13)].

7 Drug Interactions

7.13 Cannabidiol

Newly added subsection:

The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and Zortress are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of Zortress should be considered as needed when Zortress is coadministered with cannabidiol [see Dosage and Administration (2.3), Warnings and Precautions (5.22)].

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

Medication Guide

Additions and revisions underlined:

Especially tell your doctor if you take:

. . .

cannabidiol (Epidiolex)

. . .

Patient Counseling Information

Additions and revisions underlined:

Medications that Interfere with Zortress

Some medications can increase or decrease blood concentrations of Zortress. Advise patients to inform their physician if they are taking any of the following: antifungals, antibiotics, antivirals, anti-epileptic medicines including carbamazepine, phenytoin and barbiturates, herbal/dietary supplements (St. John’s Wort), cannabidiol, and/or rifampin [see Warnings and Precautions (5.14, 5.22)].

01/12/2018 (SUPPL-20)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Zortress can cause fetal harm when administered to a pregnant woman. There are limited case reports of Zortress use in pregnant women; however, these reports are insufficient to inform a drug associated risk of adverse developmental outcomes. Reproductive studies in animals have demonstrated that everolimus was maternally toxic in rabbits, and caused embryo-fetal toxicities in rats and rabbits, at exposures near or below those achieved in human transplant patients. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

Everolimus crossed the placenta and was toxic to the conceptus.

Everolimus administered daily to pregnant rats by oral gavage at 0.1 mg/kg (approximately one tenth the exposure in humans administered the lowest starting dose of 0.75 mg twice daily), from before mating through organogenesis, resulted in increased preimplantation loss and embryonic resorptions. These effects occurred in the absence of maternal toxicities.

Everolimus administered daily by oral gavage to pregnant rabbits during organogenesis resulted in abortions, maternal toxicity and lethality, and increased fetal resorptions. At these doses, exposure to everolimus (AUC) was approximately one-tenth, one-half, and one and one-half fold the exposures in humans administered the starting clinical dose, respectively.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At a dose of

0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction) and in survival of offspring (~5%). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no data regarding the presence of Zortress in human milk, the effects on breastfed infants, or the effects on milk production. Everolimus and/or its metabolites are readily transferred into milk of lactating rats at a concentration 3.5 times higher than in maternal rat serum. In pre-post-natal and juvenile studies in rats, exposure to everolimus during the postnatal period caused developmental toxicity [see Pregnancy (8.1) and Nonclinical Toxicology (13.2)]. Advise lactating women not to breastfeed because of the potential for serious adverse reactions in infants exposed to everolimus.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Contraception

Females should not be pregnant or become pregnant while receiving Zortress. Advise females of reproductive potential that animal studies have been performed showing Zortress to be harmful to the mother and developing fetus [see Pregnancy (8.1)]. Females of reproductive potential are recommended to use highly effective contraception methods while receiving Zortress and up to 8 weeks after treatment has been stopped.

Infertility

Females

Amenorrhea occurred in female patients taking Zortress [see Adverse Reactions (6.2)]. Zortress may cause pre- implantation loss in females based on animal data [see Nonclinical Toxicology (13.1)].

Female fertility may be compromised by treatment with Zortress.

Males

Zortress treatment may impair fertility in males based on human [see Warnings and Precautions (5.18), Adverse Reactions (6.2, 6.3)] and animal findings [see Nonclinical Toxicology (13.1)].

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

MEDICATION GUIDE

(additions underlined)

…

What are the possible side effects of ZORTRESS?

…

infertility, male. ZORTRESS can affect fertility in males and may affect your ability to father a child. Talk with your doctor if this is a concern for you.
infertility, female. ZORTRESS can affect fertility in females and may affect your ability to become pregnant. Talk to your doctor if this is a concern for you.
…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Pregnancy and Lactation

Advise women of childbearing age to avoid becoming pregnant throughout treatment and for 8 weeks after Zortress therapy has stopped. Zortress can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus. Also advise not to breastfeed while taking Zortress.

Male and Female Fertility

Inform male and female patients that Zortress may impair fertility.

01/12/2018 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.17 Embryo-Fetal Toxicity

(new subsection added)

Based on animal studies and the mechanism of action. Zortress may cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. 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 while using Zortress and for 8 weeks after ending treatment.

10/12/2016 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Interstitial Lung Disease/Non-Infectious Pneumonitis (addition underlined)

... Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, have occurred in patients receiving rapamycins and their derivatives, including Zortress. Most cases generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.

6 Adverse Reactions

6.2 Clinical Studies Experience (addition underlined)

Table 2. Incidence Rates of Frequent (?10% in Any Treatment Group) Adverse Reactions by Primary System Organ Class and Preferred Term after Kidney Transplantation (Safety Population*) (please refer to label)

Liver transplantation

Twenty-seven percent discontinued study drug in the Zortress group compared with 22% for the tacrolimus control group during the first 12 months of study. The most common reason for discontinuation of study medication was due to adverse reactions (19% and 11%, respectively), including proteinuria, recurrent hepatitis C, and pancytopenia in the Zortress group. At 24 months, the rate of discontinuation of study medication in liver transplant patients was greater for the Zortress group (42%) compared to tacrolimus control group (33%).

The overall incidences of serious adverse reactions were 50% (122/245) in the Zortress group and 43% (104/241) in the control group at 12 months and similar at 24 months (56% and 54% respectively).

…In the same 12 month period, 7 deaths were reported in the tacrolimus control group. Deaths occurred in both groups for a variety of reasons and were mostly associated with liver-related issues, infections and sepsis. In the following 12 months of study, four additional deaths were reported in each treatment group.

Infections

The overall incidence of infections reported as adverse reactions was 50% for Zortress and 44% in the control group and similar at 24 months (56% and 52% respectively). The types of infections were reported.

Wound Healing and Fluid Collections

Wound healing complications were reported as adverse reactions for 11% of patients in the Zortress group compared to 8% of patients in the control group up to 24 months. Pleural effusions were reported in 5% in both groups, and ascites in 4% of patients in the Zortress group and 3% in the control arm.

Neoplasms

… At 24 months the rates of malignancies were similar (10% and 11% respectively)

Lipid Abnormalities

…were reported for 24% Zortress patients, and 10% control patients at 12 months. Results were similar at 24 months (28% and 12%, respectively).

New Onset of Diabetes After Transplant (NODAT)

Of the patients without diabetes mellitus at randomization, NODAT was reported in 32% in the Zortress group compared to 29% in the control group at 12 months and similar at 24 months.

Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of =10% for patients receiving Zortress with reduced exposure tacrolimus or standard dose tacrolimus from randomization to 24 months. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 3. Incidence Rates of most Frequent (= 10% in Any Treatment Group) Adverse Reactions by Primary System Organ Class and Preferred Term and Treatment at 12 Months and 24 Months after Liver Transplantation (Safety population *) (please refer to label)

* The safety analysis population is defined as all randomized liver transplant patients who received at least one dose of treatment and had at least one post-baseline safety assessment.

Less common adverse reactions, occurring overall in =1% to <10% of either kidney or liver transplant patients treated with Zortress include:

Cardiac and Vascular Disorders: angina pectoris, atrial fibrillation, cardiac failure congestive, palpitations, tachycardia, hypertension including hypertensive crisis, hypotension, deep vein thrombosis

Endocrine Disorders: Cushingoid, hyperparathyroidism, hypothyroidism

Gastrointestinal Disorders: abdominal distention, abdominal hernia, ascites, constipation, dyspepsia, dysphagia, epigastric discomfort, flatulence, gastritis, gastroesophageal reflux disease, gingival hypertrophy, hematemesis, hemorrhoids, ileus, mouth ulceration, peritonitis, stomatitis

Hepatobiliary Disorders: hepatic enzyme increased, bile duct stenosis, bilirubin increased, cholangitis, cholestasis, hepatitis (non-infectious)

Infections and Infestations: BK virus infection [See Warnings and Precautions (5.13)], bacteremia, bronchitis, candidiasis, cellulitis, cytomegalovirus,

Investigations: blood alkaline phosphatase increased, blood creatinine increased, blood glucose increased, hemoglobin decreased, white blood cell count decreased, transaminases increased

Metabolism and Nutrition Disorders: blood urea increased, acidosis, anorexia, dehydration, diabetes mellitus [See Warnings and Precautions (5.16)], decreased appetite, fluid retention, gout, hypercalcemia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypokalemia, hypoglycemia, hypomagnesemia, hyponatremia, iron deficiency, new onset diabetes mellitus, vitamin B12 deficiency

Musculoskeletal and Connective Tissues Disorders: arthralgia, joint swelling, muscle spasms, muscular weakness, musculoskeletal pain, myalgia, osteoarthritis, osteonecrosis, osteopenia, osteoporosis, spondylitis

Renal and Urinary Disorders: bladder spasm, hydronephrosis, micturation urgency, nephritis interstitial, nocturia, pollakiuria, polyuria, proteinuria

Reproductive System and Breast Disorders: amenorrhea, benign prostatic hyperplasia, erectile dysfunction, ovarian cyst, scrotal edema

Respiratory, Thoracic, Mediastinal Disorders: atelectasis, bronchitis, dyspnea, cough, epistaxis, lower respiratory tract infection, nasal congestion, oropharyngeal pain, pleural effusions, pulmonary edema, rhinorrhea, sinus congestion, wheezing

Skin and Subcutaneous Tissue Disorders: acne, alopecia, dermatitis acneiform, ecchymosis, hirsutism, hyperhydrosis, hypertrichosis, night sweats, pruritus, rash

Vascular Disorders: venous thromboembolism (including deep vein thrombosis), phlebitis, pulmonary embolism

Less common, serious adverse reactions occurring overall in <1% of either kidney or liver transplant patients treated withZortress include:

PancreatitisThrombotic Microangiopathy (TMA), Thrombotic Thrombocytopenic Purpura (TTP), and Hemolytic Uremic Syndrome (HUS)

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

MEDICATION GUIDE (addition underlined)

What should I tell my doctor before taking ZORTRESS?

Before taking ZORTRESS, tell your doctor if you:

are pregnant or plan to become pregnant. It is not known if ZORTRESS will harm your unborn baby. Talk with your doctor if you are pregnant or plan to become pregnant .Women who may become pregnant should use effective birth control (contraception) while taking ZORTRESS and for 8 weeks after stopping ZORTRESS.