Glucarpidase

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# Overview
Glucarpidase is an methotrexate rescue agent that is FDA approved for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function.   Common adverse reactions include paraesthesia, flushing, nausea and/or vomiting, hypotension, and headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function.
- Glucarpidase  is not indicated for use in patients who exhibit the expected clearance of methotrexate (plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) or those with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate.
- Administer Glucarpidase  as a single intravenous injection of 50 Units per kg.
- Administer Glucarpidase  intravenously as a bolus injection over 5 minutes. Flush intravenous line before and after administration of Glucarpidase .
- Reconstitute the contents of the vial with 1 mL of sterile saline for injection, USP.
- Roll and tilt the vial gently to mix. Do not shake.
- Inspect the vial and discard Glucarpidase  if the solution is not clear, colorless, and free of particulate matter.
- Use reconstituted Glucarpidase  immediately or store under refrigeration at 36 to 46F (2 to 8C) for up to 4 hours if not used immediately. Glucarpidase  contains no preservative and is supplied as a single-use vial. *Discard any unused product.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase  in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Glucarpidase  in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Glucarpidase  in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase  in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Glucarpidase  in pediatric patients.

# Contraindications
- None

# Warnings
- Serious allergic reactions occurred in less than 1% of patients .
- Methotrexate concentrations within 48 hours following administration of Glucarpidase  can only be reliably measured by a chromatographic method. DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) is an inactive metabolite of methotrexate resulting from treatment with Glucarpidase . DAMPA interferes with the measurement of methotrexate concentration using immunoassays resulting in an erroneous measurement which overestimates the methotrexate concentration. Due to the long half-life of DAMPA (t1/2 of approximately 9 hours), measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following Glucarpidase  administration .
- Continue to administer leucovorin after Glucarpidase . Do not administer leucovorin within 2 hours before or after a dose of Glucarpidase  because leucovorin is a substrate for Glucarpidase  .
- For the first 48 hours after Glucarpidase , administer the same leucovorin dose as given prior to Glucarpidase . Beyond 48 hours after Glucarpidase , administer leucovorin based on the measured methotrexate concentration. Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days.
- Continue hydration and alkalinization of the urine as indicated.

# Adverse Reactions

## Clinical Trials Experience
- Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with Glucarpidase  are paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache.
- Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of Glucarpidase  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 treated with Glucarpidase  is confounded by the population in which it was studied, patients with toxic plasma methotrexate levels due to impaired renal function. Adverse reactions related to toxic methotrexate levels due to prolonged methotrexate clearance include myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure.
- The safety of Glucarpidase  is based on data from 290 patients who were treated in 2 single-arm, open-label, multicenter trials enrolling patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was greater than 50 mol/L at 24 hours, greater that 5 mol/L at 48 hours, or greater than 2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration and there was a 2-fold or greater increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate level was greater than 10 mol/L more than 42 hours after the start of the methotrexate or the plasma level was greater than 2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate and the serum creatinine was greater than 1.5 times the upper limit of normal or the creatinine clearance was less than 60 mL/min at least 12 hours following methotrexate administration.
- Study 1, conducted by the National Cancer Institute (NCI), enrolled 184 patients; safety information is available for 149 patients. Glucarpidase  was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. Patients with pre-Glucarpidase  methotrexate concentrations >100 mol/L were to receive a second dose of Glucarpidase  48 hours after the first 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 two hours before or after Glucarpidase .
- In Study 1, Glucarpidase -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 information was abstracted and categorized using the National Cancer Institute (NCI) "Common Terminology Criteria for Adverse Events" (CTCAE) version 3 scale.
- The Study 1 population enrolled patients with a median age of 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. One (n=106) or 2 (n= 30) doses of Glucarpidase  were administered intravenously; the number of doses was not specified in 13 patients. Doses ranged from 18 to 98 Units/kg, with a median dose of 49 Units/kg.
- Study 2 is an ongoing expanded access program. At the time of data cut-off, 243 patients were enrolled and safety data was available for 141 patients. Glucarpidase  was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. The criterion for allowing patients to receive a second glucarpidase dose was not specified in the protocol. 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 two hours before or after Glucarpidase .
- Study 2 enrolled patients with a median age of 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. One (n=122) or 2 (n= 18) doses of Glucarpidase  were administered intravenously; the number of doses was not specified for 1 patient. Doses ranged from 6 to 189 Units/kg, with a median dose of 50 Units/kg.
- In Study 2 only Glucarpidase -related adverse reactions were collected and severity was graded according to NCI CTCAE version 3.
- Among the 290 patients included in the safety evaluation of Glucarpidase , there were 8 deaths within 30 days of Glucarpidase  exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to Glucarpidase . Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1).
- As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials, 121 patients who received one (n=99), two (n=21), or three (n=1) doses of Glucarpidase  were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following Glucarpidase  administration, of which 19 received a single dose of Glucarpidase  and 6 received two doses of Glucarpidase . 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 Glucarpidase . However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.
- 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 to Glucarpidase  with the incidence of antibodies to other products may be misleading.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Glucarpidase  in the drug label.

# Drug Interactions
- Leucovorin is a substrate for Glucarpidase . Do not administer leucovorin within 2 hours before or after a dose of Glucarpidase . No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patients pre-Glucarpidase  methotrexate concentration .
- Other potential exogenous substrates of Glucarpidase  may include reduced folates and folate antimetabolites.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well controlled studies with Glucarpidase  in pregnant women and animal reproduction studies have not been conducted with Glucarpidase . Therefore, it is not known whether Glucarpidase  can cause fetal harm when administered to a pregnant woman. Glucarpidase  should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glucarpidase  in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Glucarpidase  during labor and delivery.

### Nursing Mothers
- It is not known if Glucarpidase  is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Glucarpidase  is administered to a nursing woman.

### Pediatric Use
- The effectiveness of Glucarpidase  in pediatric patients was established in Study 1. Of the 22 patients in the efficacy dataset in Study 1, 12 were pediatric patients with ages ranging from 5 to 16 years. Three of the six pediatric patients with a pre-Glucarpidase  methotrexate concentration of 1-50 mol/L achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, while none of the six pediatric patients with a pre-Glucarpidase  methotrexate concentration >50 mol/L achieved a RSCIR .
- The pooled clinical safety database for Glucarpidase  included data for 147 patients from 1 month up to 17 years of age. No overall differences in safety were observed between these patients and adult patients.

### Geriatic Use
- Of the total number of 290 patients in clinical studies of Glucarpidase , 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 patients.

### Gender
There is no FDA guidance on the use of Glucarpidase  with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Glucarpidase  with respect to specific racial populations.

### Renal Impairment
- No dose adjustment of Glucarpidase  is recommended for patients with renal impairment

### Hepatic Impairment
- No specific studies of Glucarpidase  in patients with hepatic impairment have been conducted.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Glucarpidase  in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Glucarpidase  in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
There is limited information regarding Monitoring of Glucarpidase  in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Glucarpidase  in the drug label.

# Overdosage
- There are no known cases of overdose with Glucarpidase .

# Pharmacology

## Mechanism of Action
- Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase  converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. Glucarpidase  provides an alternative non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.

## Structure
- Glucarpidase  (glucarpidase) is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. Each potency Unit corresponds to the enzymatic cleavage of 1 mol/L of methotrexate per minute at 37C.
- Glucarpidase  is supplied as a sterile, preservative-free, white lyophilized powder in single-use vials. Each vial contains 1,000 Units of glucarpidase, lactose monohydrate (10 mg), Tris-HCl (0.6 mg) and zinc acetate dihydrate (0.002 mg).

## Pharmacodynamics
- Plasma methotrexate concentrations within 48 hours following administration of Glucarpidase  can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays. Following administration of Glucarpidase  50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by  97% within 15 minutes in all 22 treatment-evaluable patients, and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients

## Pharmacokinetics
- The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of Glucarpidase  50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA.
- Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours. The mean Cmax was 3.3 g/mL and the mean area under the curve (AUC0-inf) was 23.3 gh/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t1/2 of 9 hours.
- The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in four subjects with severe renal impairment (creatinine clearance <30 mL/min). Following an intravenous dose of 50 Units/kg of Glucarpidase , the mean pharmacokinetic parameters were similar to those observed in healthy subjects except for a longer t1/2 of 8.2 hours as compared to 5.6 hours in healthy subjects by the enzymatic assay.
- In a study of cancer patients receiving a high-dose methotrexate (1 g/m2) and leucovorin rescue regimen, intravenous administration of 50 Units/kg Glucarpidase  2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52%, and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93%

## Nonclinical Toxicology
- Glucarpidase  has not been evaluated in animals for carcinogenic or mutagenic potential or for impairment of fertility.

# Clinical Studies
- The efficacy of Glucarpidase  was evaluated in a subset consisting of 22 treatment-evaluable patients enrolled in Study 1. Study 1 was a single-arm, open-label study in patients who had markedly delayed methotrexate clearance (defined as more than 2 standard deviations greater than the mean excretion curve for methotrexate) secondary to renal dysfunction. All patients received Glucarpidase  50 Units/kg as an intravenous injection over 5 minutes; those patients with pre-Glucarpidase  methotrexate concentrations >100 mol/L were to receive a second dose of Glucarpidase  48 hours after the first 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 two hours before or after Glucarpidase .
- Efficacy was evaluated in a subset of patients enrolled in Study 1 who met the inclusion criteria for the study, had a pre-Glucarpidase  methotrexate concentration >1 mol/L, and had both pre- and post-treatment plasma samples available for determination of methotrexate concentration by a chromatographic method analysis. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, defined as an attainment of plasma methotrexate concentration 1 mol/L at 15 minutes that was sustained for up to 8 days following the initial injection.
- Of the 22 patients in the efficacy dataset, the median age was 15.5 years (5 to 84 years); 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia or lymphoma (45%).
- Ten of the 22 patients achieved RSCIR . Of the 12 patients who failed to achieve RSCIR, 5 patients (23%) attained a transient plasma methotrexate concentration of  1 mol/L. In these 5 patients, the median increase of plasma methotrexate concentration from their nadir was 1.4 mol/L (0.3 to 2.5 mol/L).
- Table 2 summarizes the results of RSCIR and exploratory analyses following the first dose administration of Glucarpidase . An exploratory analysis in subgroups determined by pre-Glucarpidase  methotrexate concentration suggests that the likelihood of attaining a RSCIR following the first Glucarpidase  injection correlates with the pre-Glucarpidase  methotrexate concentration (Table 2). In an additional exploratory analysis, all 9 patients with pre-glucarpidase methotrexate concentrations >50 mol/L achieved greater than a 95% reduction in methotrexate concentrations for up to 8 days following the initial injection of Glucarpidase  although none of them achieved a RSCIR
- Six of the seven patients with pre-first dose Glucarpidase  methotrexate concentrations >100 mol/L received a second 50 Units/kg dose of Glucarpidase  administered 48 hours after the first dose. Among them, none of the four patients with pre-second dose Glucarpidase  methotrexate concentrations >1 mol/L achieved a RSCIR. The remaining two patients achieved a RSCIR but their pre-second dose Glucarpidase  methotrexate concentrations were already 1 mol/L.
- There are no controlled trials comparing Glucarpidase  plus supportive care to supportive care measures alone in patients with toxic plasma methotrexate concentrations due to impaired renal function, therefore there are no data regarding the effect of Glucarpidase  on survival or toxic deaths due to methotrexate. Glucarpidase  did not prevent fatal methotrexate toxicity in 3% of patients in the safety population.

# How Supplied
- Glucarpidase  is supplied as a sterile, preservative-free white lyophilized powder in an individually packaged glass vial closed with a bromo butyl elastomeric stopper and blue flip-off seal.
1,000 Units of glucarpidase per vial (1 vial per carton) NDC 50633-210-11

## Storage
- Store Glucarpidase  at 36F to 46F (2C to 8C). Do not freeze. Do not use Glucarpidase  after the expiration date on the vial.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Glucarpidase Patient Counseling Information in the drug label.

# Precautions with Alcohol
- Alcohol-Glucarpidase  interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- VORAXAZE

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price