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.

MIRCERA (BLA-125164)

(METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA)

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

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04/30/2024 (SUPPL-89)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

A second open-label, single-arm, multicenter study was conducted to ascertain the optimal starting dose of Mircera given subcutaneously for the maintenance treatment of anemia in 40 pediatric patients (ages 3 months to 17 years) with CKD on dialysis or not on dialysis. Patients completing the 20 weeks of treatment (core period) with Hb within ±1 g/dL of their baseline Hb and within the target range of 10 to 12 g/dL, were eligible to enter an optional 24-week safety extension period. Mircera was administered subcutaneously once every 4 weeks for the duration of the study. Thirty-eight (38) patients were exposed to Mircera for 20 weeks, and 21 patients were exposed to Mircera for 44 weeks. Overall, the pattern of adverse events reported was similar to the established safety profile of Mircera in adult patients and the patients aged 5 to 17 years in the previous intravenous study.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

The safety and effectiveness of intravenous and subcutaneous Mircera for the treatment of anemia due to CKD have been established in pediatric patients 3 months to 17 years of age on dialysis and not on dialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA. The use of Mircera in this pediatric age group is supported by evidence from adequate and well-controlled studies of Mircera in adults, a dose-finding study in 64 pediatric patients 5 to 17 years of age with CKD on hemodialysis and a subcutaneous dose-finding study in 40 patients 3 months to 17 years of age with CKD on dialysis or not on dialysis. The adverse reaction profile observed in pediatric patients was consistent with the safety profile found in adults. The safety and effectiveness of Mircera have not been established in patients less than 3 months of age [see Adverse Reactions (6.1) and Clinical Studies (14.2)].

The safety and effectiveness of Mircera have not been established for treatment of anemia in pediatric patients whose hemoglobin level has not been previously stabilized by treatment with an ESA.

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

Medication Guide

Additions and revisions underlined:

What is the most important information I should know about Mircera?

Mircera may cause serious side effects that can lead to death, including:

For people with cancer:

Mircera is not for use to treat anemia that is caused by cancer chemotherapy. If you have certain cancers, your tumor

may grow faster, and you may die sooner if you take Mircera.

For people with anemia from chronic kidney disease (CKD) who take Mircera:

• Serious heart problems, such as heart attack or heart failure, and stroke. You may die sooner if you are

treated with Mircera to increase red blood cells (RBCs) to near the same level found in healthy people.

• Blood clots. Blood clots may happen at any time while taking Mircera. Your chance of getting a blood clot that is

serious and life threatening is higher if you have cancer.

. . .

If you and your healthcare provider decide that you should take Mircera, you should be prescribed the smallest dose of Mircera that is necessary to reduce your chance of needing RBC transfusions.

. . .

Mircera is a prescription medicine used to treat anemia in certain people with chronic kidney disease (CKD).

Mircera may be used to treat anemia if it is caused by CKD in:

• adults who may or may not be on dialysis

• children 3 months to 17 years of age who may or may not be on dialysis who are switching from another

erythropoiesis-stimulating agent (ESA) after their hemoglobin level is stable

. . .

It is not known if Mircera is safe and effective in children who:

• are under 3 months of age or

• have received another ESA medicine and do not have stable hemoglobin or

• have not been treated with another ESA medicine to correct anemia

. . .

• Have had serious allergic reactions to Mircera. See “What are the possible side effects of Mircera?” for more

information.

. . .

Your healthcare provider may lower your dose, or temporarily stop Mircera and restart it at a lower dose, if

your hemoglobin levels get too high during treatment.

. . .

• Your healthcare provider will do regular blood tests during treatment to check your hemoglobin levels.

. . .

Mircera may cause serious side effects, including:

. . .

• Severe skin reactions. Severe skin reactions can happen during treatment. Signs and symptoms of severe skin

reactions with Mircera may include skin rash with itching, hives, blisters, skin sores, peeling, or areas of skin

coming off. If you develop any signs or symptoms of skin reactions, stop using Mircera and call your healthcare

provider or get medical help right away.

. . .

• Throw away (discard) Mircera after 30 days if it has been stored at room temperature.

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

. . .

Administer Mircera under the direct supervision of a healthcare provider or, in situations where a patient or caregiver has been trained to administer Mircera at home, provide instruction on the proper use of Mircera

06/07/2018 (SUPPL-78)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

Table 3: Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients With CKD

5.2 Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control

Table 4: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control some changes to this table; please refer to label for complete information.

Newly added subsection:

5.8 Severe Cutaneous Reactions

Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including Mircera) in the postmarketing setting. Discontinue Mircera therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.

6 Adverse Reactions

Addition of the following to the bulleted listing:

Severe Cutaneous Reactions

6.1 Clinical Trials Experience

Adult Patients

Additions and/or revisions underlined:

Table 5: Adverse Reactions Occurring in greater than or equal to 5% of CKD Patients

Newly added information:

Pediatric Patients

In an open-label, multiple dose study, 64 pediatric patients (ages 5 to 17 years) with CKD who were on hemodialysis and who had stable hemoglobin levels while previously receiving another ESA (epoetin alfa/beta or darbepoetin alfa) were then converted to Mircera administered intravenously once every 4 weeks for 20 weeks (core study period). Patients who completed the core study period with hemoglobin within ± 1 g/dL of their baseline hemoglobin and within the target range of 10 to 12 g/dL were eligible to enter an optional 52-week safety extension period (total duration of treatment, up to 73 weeks). In the extension period, 25 (out of 37) patients were treated for at least an additional 5 months. During the whole study (core study and safety extension), 33 patients were exposed to Mircera for at least 6 months and 19 were exposed for greater than 15 months.

All reported adverse reactions regardless of causality (more than 5% incidence) in the pediatric population included headache (22%), nasopharyngitis (22%), hypertension (19%), vomiting (11%), bronchitis (9%),

abdominal pain (8%), arteriovenous fistula thrombosis (6%), cough (6%), device related infection (6%),

hyperkalemia (6%), pharyngitis (6%), pyrexia (6%), thrombocytopenia (6%), and thrombosis in device (6%).

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

Available data from a small number of published case reports and postmarketing experience with Mircera use in pregnancy are insufficient to identify a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease is associated with maternal and embryo-fetal risks. In animal reproduction studies, administration of methoxy polyethylene glycol- epoetin beta to rats and rabbits during pregnancy and lactation adversely affected offspring at doses 17-fold and greater than the recommended human dose.

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 risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease Associated Maternal and/or Embryo-Fetal Risk

Pregnancy in women with chronic kidney disease has been associated with adverse outcomes including hypertension, pre-eclampsia, miscarriage, premature birth, low-birth-weight, polyhydramnios, and intrauterine growth restriction.

Data

When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to rats and rabbits during gestation (including the period of organogenesis), bone malformation was observed in both species at 50 mcg/kg once every three days (corresponding to 500 mcg/kg/month or 417-fold the recommended human dose) in studies of embryo-fetal development. This effect was observed as missing caudal vertebrae … every three days and higher, corresponding to 50 mcg/kg/month or 42-fold the recommended human dose, methoxy polyethylene glycol-epoetin …

… Increased deaths and significant reduction in the growth rate of the F1 generation were observed during lactation and early post weaning period at 20 and 50 mcg/kg/dose, corresponding to 80 and 200 mcg/kg/month or 67- and 167-fold the recommended human dose. A significant reduction in the growth rate of the F1 generation was evident already at 5 mcg/kg/dose, corresponding to 20 mcg/kg/month or 17-fold the recommended human dose. However, no remarkable effect on reflex …

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no data on the presence of methoxy polyethylene glycol-epoetin beta in human milk, the effects on the breastfed child, or the effects on milk production. However, endogenous erythropoietin is present in human milk. In rats, methoxy polyethylene glycol-epoetin beta was present in maternal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of Mircera to a child during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mircera and any potential adverse effects on the breastfed child from Mircera or from the underlying maternal condition.

Data

A dose of methoxy polyethylene glycol-epoetin beta approximately 3-fold greater than the recommended human dose was administered to lactating rats. Methoxy polyethylene glycol-epoetin beta was detected in maternal milk 4 hours post dose and reached maximum concentration 48 hours post dose. The maximum amount of methoxy polyethylene glycol-epoetin beta in milk was about 10-fold lower than in serum. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

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

MEDICATION GUIDE

Extensive changes; please refer to label for complete information.