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.

VORAXAZE (BLA-125327)

(GLUCARPIDASE)

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

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08/13/2019 (SUPPL-64)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS AND PRECAUTIONS

Additions and/or revisions underlined:

Serious Hypersensitivity Reactions

Serious hypersensitivity reactions occurred in less than 1% of patients.

Interference with Immunoassay Measurements of Methotrexate

DAMPA (4-deoxy-4-amino-N10- methylpteroic acid), an inactive metabolite of methotrexate formed following VORAXAZE administration, interferes with the measurement of methotrexate concentration using immunoassays. This interference results in an overestimation of the methotrexate concentration. Based on the half-life of DAMPA (about 9 hours), VORAXAZE may interfere with the measurement of methotrexate concentration for up to 48 hours following a VORAXAZE dose.

When measuring methotrexate concentration following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay.

6 Adverse Reactions

ADVERSE REACTIONS

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

· Serious Hypersensitivity Reactions.

Clinical Trials Experience

Additions and/or revisions underlined:

Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of VORAXAZE cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

The evaluation of adverse reactions in patients who received VORAXAZE was confounded, because patients had toxic plasma methotrexate concentration due to prolonged methotrexate clearance, which is associated with myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure.

The safety of VORAXAZE is based on data from 290 patients who were enrolled in Study 1 or Study 2, two single-arm, open-label, multicenter studies conducted in patients who had markedly delayed methotrexate clearance due to impaired renal function. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was >50 µmol/L at 24 hours, >5 µmol/L at 48 hours, or >2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration; and there was a > 2-fold increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate concentration was >10 µmol/L more than 42 hours after the start of the methotrexate or the plasma methotrexate concentration was >2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate; and the serum creatinine was >1.5 times the upper limit of normal (ULN) or the creatinine clearance (CLcr) was <60 mL/min at least 12 hours following methotrexate administration.

Safety data was available for 149 patients enrolled in Study 1. The protocol specified that patients with pre-VORAXAZE methotrexate concentration >100 ?mol/L were to receive a second VORAXAZE dose 48 hours after the first dose; that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin; and that leucovorin administration be adjusted to ensure that it was not administered within 2 hours before or after a VORAXAZE dose. VORAXAZE-related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as “glucarpidase toxicity”. Additional safety information was collected from clinical records submitted by treating physicians. This safety information was abstracted and categorized using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3. One (n=106) or 2 (n= 30) doses of VORAXAZE were administered; the number of doses was not specified for 13 patients. Doses ranged from 18 Units/kg to 98 Units/kg, with a median dose of 49 Units/kg. The median age was 18 years (1 month to 85 years); 63% were male; and the underlying malignancies were osteosarcoma/sarcomas in 32% and leukemia or lymphoma in 63% of patients.

Safety data was available for 141 patients enrolled in Study 2. The protocol did not specify the criterion for allowing patients to receive a second VORAXAZE dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin and that leucovorin administration be adjusted to ensure that it was not administered within 2 hours before or after VORAXAZE. VORAXAZE-related adverse reactions were collected and severity was graded according to NCI CTCAE version 3. One (n=122) or 2 (n= 18) doses of VORAXAZE were administered; the number of doses was not specified for 1 patient. Doses ranged from 6 Units/kg to 189 Units/kg, with a median dose of 50 Units/kg. The median age was 17 years (6 months to 85 years); 64% were male; and the underlying malignancies were osteogenic sarcoma in 32% and leukemia or lymphoma in 62% of patients.

Among the 290 patients, 8 deaths occurred within 30 days of VORAXAZE exposure that were not related to progressive disease.

The most common adverse reactions (reported in >1%) were paresthesia, flushing, and nausea and/or vomiting. Table 1 summarizes select adverse reactions; adverse reactions likely associated with toxic methotrexate plasma concentrations, such as hematological, renal and hepatic adverse reactions, were not included in this table.

Data in Table has been changed; please refer to label for complete information.

Immunogenicity

Additions and/or revisions underlined:

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other glucarpidase products may be misleading.

In clinical trials, 121 patients who received one (n=99), 2 (n=21), or 3 (n=1) doses of VORAXAZE were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following VORAXAZE administration, of which 19 received 1 dose of VORAXAZE and 6 received 2 doses of VORAXAZE. Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti- glucarpidase antibodies.

Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti- glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of VORAXAZE; however, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

7 Drug Interactions

Additions and/or revisions underlined:

i. Effects of VORAXAZE on Leucovorin

VORAXAZE can decrease leucovorin concentration, which may decrease the effect of leucovorin rescue unless leucovorin is dosed as recommended.

VORAXAZE may also reduce the concentrations other folate analogs or folate analog metabolic inhibitors.

ii. Effect of VORAXAZE on Measurement of Methotrexate Concentration

DAMPA (4-deoxy-4-amino-N10- methylpteroic acid), an inactive metabolite of methotrexate formed following VORAXAZE administration, interferes with the measurement of methotrexate concentration using immunoassays. This interference results in an overestimation of the methotrexate concentration. Based on the half-life of DAMPA, VORAXAZE may interfere with the measurement of methotrexate concentrations for approximately 48 hours following a VORAXAZE dose.

When measuring methotrexate concentration following a VORAXAZE dose, a chromatographic method is preferred over an immunoassay.

8 Use in Specific Populations

Geriatric Use

Additions and/or revisions underlined:
Of the total number of 290 patients in clinical studies of VORAXAZE, 15% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger adult patients.

Lactation

Newly added subsection:

Risk Summary

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

VORAXAZE is administered in combination with methotrexate. Refer to methotrexate prescribing information for additional information.

Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of VORAXAZE have been established in pediatric patients. Use of VORAXAZE for this indication is supported by evidence from a single-arm, open-label study in adult and pediatric patients 5 years of age and older with additional safety data in pediatric patients 1 to 17 years of age as described below.

Of the 22 patients in the efficacy dataset in Study 1, 12 were pediatric patients with ages ranging from 5 years to 16 years. Three of the 6 pediatric patients with a pre-VORAXAZE methotrexate concentration of 1 mmol/L to 50 mmol/L achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, while none of the 6 pediatric patients with a pre-VORAXAZE methotrexate concentration >50 mmol/L achieved a RSCIR.

One-hundred forty-seven pediatric patients from 1 month to 17 years received VORAXAZE in Study 1 and Study 2. No overall differences in safety were observed between these patients and adult patients.

Pregnancy

Additions and/or revisions underlined:

Risk Summary

There are no available data on VORAXAZE use in pregnant women or animal reproduction studies to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

VORAXAZE is administered in combination with methotrexate, which can cause embryo-fetal harm. Refer to methotrexate prescribing information for additional information.

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

Renal Impairment

Additions and/or revisions underlined:
A study of the pharmacokinetics of glucarpidase in the absence of methotrexate in 4 subjects with severe renal impairment (CLcr <30 mL/min) showed that the mean pharmacokinetic parameters were similar to those observed in healthy subjects.
On this basis, no dose adjustment of VORAXAZE is recommended for patients with renal impairment.

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

PATIENT COUNSELING INFORMATION

Serious Hypersensitivity Reactions

Inform patients that hypersensitivity reactions, including potentially serious reactions, may occur following a dose of VORAXAZE and to immediately report any signs and symptoms of infusion reactions

Administration

Inform patients of the importance of continued monitoring of plasma methotrexate concentration and renal function at the appropriate times after discharge from the hospital.