Uricozyme

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Uricozyme uses


WARNING: HYPERSENSITIVITY REACTIONS, HEMOLYSIS, METHEMOGLOBINEMIA, AND INTERFERENCE WITH URIC ACID MEASUREMENTS

WARNING: HYPERSENSITIVITY REACTIONS, HEMOLYSIS, METHEMOGLOBINEMIA, AND INTERFERENCE WITH URIC ACID MEASUREMENTS

See full prescribing information for complete boxed warning .

  • Hypersensitivity Reactions: Uricozyme can cause serious and fatal hypersensitivity reactions including anaphylaxis. Immediately and permanently discontinue Uricozyme if a serious hypersensitivity reaction occurs (4, 5.1, 6.2).
  • Hemolysis: Do not administer Uricozyme to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue Uricozyme if hemolysis occurs. Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Uricozyme therapy (4, 5.2).
  • Methemoglobinemia: Uricozyme can result in methemoglobinemia in some patients. Immediately and permanently discontinue Uricozyme if methemoglobinemia occurs (4, 5.3).
  • Interference with uric acid measurements: Uricozyme enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in pre-chilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection (5.4).

Hypersensitivity Reactions

Uricozyme® can cause serious and fatal hypersensitivity reactions including anaphylaxis. Immediately and permanently discontinue Uricozyme in patients who experience a serious hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.1), Adverse Reactions (6.2) ].

Hemolysis

Do not administer Uricozyme to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue Uricozyme in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Uricozyme [see Contraindications (4), Warnings and Precautions (5.2) ].

Methemoglobinemia

Uricozyme can result in methemoglobinemia in some patients. Immediately and permanently discontinue Uricozyme in patients developing methemoglobinemia [see Contraindications (4), Warnings and Precautions (5.3) ].

Interference with Uric Acid Measurements

Uricozyme enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in pre-chilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection [see Warnings and Precautions (5.4) ].

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1 INDICATIONS AND USAGE

Uricozyme ® is indicated for the initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.

Limitation of use: Uricozyme is indicated only for a single course of treatment [see Warnings and Precautions (5.1) ].

Uricozyme is a recombinant urate-oxidase indicated for initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid (1).

Limitation of use: Uricozyme is indicated only for a single course of treatment (1).

2 DOSAGE AND ADMINISTRATION

  • Administer at 0.2 mg/kg as an intravenous infusion over 30 minutes daily for up to 5 days.
  • Do not administer as an intravenous bolus (2.3).

2.1 Dosage

The recommended dose of Uricozyme is 0.2 mg/kg as a 30 minute intravenous infusion daily for up to 5 days. Dosing beyond 5 days or administration of more than one course is not recommended.

2.2 Reconstitution Procedure

  • Uricozyme must be reconstituted with the diluent provided in the carton.
  • Reconstitute the 1.5 mg vial of Uricozyme with 1 mL of diluent. Reconstitute the 7.5 mg vial of Uricozyme with 5 mL of diluent. Mix by swirling gently. Do not shake or vortex.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard solution if particulate matter is visible or product is discolored.

2.3 Further Dilution and Administration

  • Administer Uricozyme as an intravenous infusion only
  • Inject the calculated dose of reconstituted Uricozyme solution into an infusion bag containing the appropriate volume of 0.9% sterile sodium chloride, to achieve a final total volume of 50 mL.
  • Infuse over 30 minutes through a separate line or flush line with at least 15 mL of normal saline prior to and after Uricozyme infusion.
  • Do not use filters during infusion of reconstituted Uricozyme drug product.
  • Store reconstituted or diluted solution at 2–8°C.
  • Discard unused product solution 24 hours following reconstitution.
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3 DOSAGE FORMS AND STRENGTHS

  • For injection: 1.5 mg, lyophilized powder in single-dose vial for reconstitution
  • For injection: 7.5 mg, lyophilized powder in single-dose vial for reconstitution
  • For injection, 1.5 mg, lyophilized powder in single-dose vial (3)
  • For injection, 7.5 mg lyophilized powder in single-dose vial (3)

4 CONTRAINDICATIONS

Uricozyme is contraindicated in patients with a history of anaphylaxis or severe hypersensitivity to Uricozyme or in patients with development of hemolytic reactions or methemoglobinemia with Uricozyme [see Boxed Warning, Warnings and Precautions (5) ].

Uricozyme is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD) [see Boxed Warning, Warnings and Precautions (5.2) ].

  • History of the following reactions to Uricozyme: anaphylaxis, severe hypersensitivity, hemolysis, methemoglobinemia (4).
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency (4).

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Uricozyme can cause serious and fatal hypersensitivity reactions including anaphylaxis. In clinical studies, anaphylaxis was reported in <1% patients receiving Uricozyme. This can occur at any time during treatment including the first dose. Signs and symptoms of these reactions include bronchospasm, chest pain and tightness, dyspnea, hypoxia, hypotension, shock, and urticaria. Immediately and permanently discontinue Uricozyme administration in any patient developing clinical evidence of a serious hypersensitivity reaction [see Boxed Warning, Contraindications, Adverse Reactions (6.2) ].

The safety and efficacy of Uricozyme have been established only for a single course of treatment once daily for 5 days.

5.2 Hemolysis

Uricozyme is contraindicated in patients with G6PD deficiency because hydrogen peroxide is one of the major by-products of the conversion of uric acid to allantoin. In clinical studies, hemolysis occurs in <1% patients receiving Uricozyme; severe hemolytic reactions occurred within 2–4 days of the start of Uricozyme. Immediately and permanently discontinue Uricozyme administration in any patient developing hemolysis. Institute appropriate patient monitoring and support measures (e.g., transfusion support). Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Uricozyme [see Boxed Warning, Contraindications (4) ].

5.3 Methemoglobinemia

In clinical studies, methemoglobinemia occurred in <1% patients receiving Uricozyme. These included cases of serious hypoxemia requiring intervention with medical support measures. It is not known whether patients with deficiency of cytochrome b5 reductase or of other enzymes with antioxidant activity are at increased risk for methemoglobinemia or hemolytic anemia. Immediately and permanently discontinue Uricozyme administration in any patient identified as having developed methemoglobinemia. Institute appropriate monitoring and support measures (e.g., transfusion support, methylene-blue administration) [see Boxed Warning, Contraindications (4) ].

5.4 Laboratory Test Interference

At room temperature, Uricozyme causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. Special sample handling procedure must be followed to avoid ex vivo uric acid degradation [see Boxed Warning, Drug Interactions (7) ].

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6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

  • Anaphylaxis [see Boxed Warning, Contraindications, Warnings and Precautions (5.1) ]
  • Hemolysis [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.2) ]
  • Methemoglobinemia [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.3) ]

Most common adverse reactions (incidence ≥20%), occurring in patients with hematological or solid tumor malignancy and treated with anti-cancer therapy are vomiting, nausea, fever, peripheral edema, anxiety, headache, abdominal pain, constipation, diarrhea, hypophosphatemia, pharyngolaryngeal pain, and increased alanine aminotransferase. (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Uricozyme in 265 pediatric and 82 adult patients enrolled in one active-controlled trial (Study 1), two uncontrolled trials (Studies 2 and 3), and an uncontrolled safety trial (n=82). Additional data were obtained from an expanded access program of 356 patients, for whom data collection was limited to serious adverse reactions. Among these 703 patients 63% were male, the median age was 10 years (range 10 days to 88 years), 73% were Caucasian, 9% African, 4% Asian, and 14% other/unknown.

Among the 347 patients for whom all adverse reactions regardless of severity were assessed, the most frequently observed adverse reactions (incidence ≥10%) were vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%). In Study 1, an active control study, the following adverse reactions occurred more frequently in Elitek-treated subjects than allopurinol-treated subjects: vomiting, fever, nausea, diarrhea, and headache. Although the incidence of rash was similar in the two arms, severe rash was reported only in one Elitek-treated patient.

Further studies, including one-active controlled study (Study 4) and four supportive studies, have been conducted in adult patients. In these studies, Uricozyme was administered to a total of 434 adult patients (58% male, 42% female; median age 56 years [range 18 years to 89 years]; 52% Caucasian, 7% African, 14% Asian, 28% other/unknown).

Of these 434 patients, 275 adult patients with leukemia, lymphoma, or solid tumor malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomized in an open label trial receiving either Uricozyme alone, Uricozyme in combination with allopurinol, or allopurinol alone (Study 4).

A drug-related adverse reaction in Study 4 of any grade was experienced in 4.3% of Elitek-treated patients, 5.4% of Elitek/allopurinol-treated patients, and 1.1% of allopurinol-treated patients.

Table 1 presents the per-patient incidence of adverse reactions by study arm in Study 4.

Adverse ReactionEvents were reported and graded according to NCI-CTC version 3.0 and presented as preferred terms MedDRA version 10.1. Uricozyme

(n=92)

Uricozyme / Allopurinol

(n=92)

Allopurinol

(n=91)

All

Grades

%

Grades

3,4

%

All

Grades

%

Grades

3,4

%

All

Grades

%

Grades

3,4

%

Overall incidence ≥10% in any Uricozyme arm and the difference between any Uricozyme arm versus the allopurinol arm ≥5%.
Nausea 57.6 1.1 60.9 1.1 54.9 2.2
Peripheral edema 50 2.2 43.5 3.3 42.9 6.6
Vomiting 38 1.1 37 0 30.8 1.1
Anxiety 23.9 3.3 17.4 0 17.6 0
Abdominal pain 21.7 3.3 33.7 4.3 25.3 2.2
Hypophosphatemia 17.4 4.3 22.8 6.5 16.5 6.6
Hyperbilirubinemia 16.3 3.3 14.1 2.2 7.7 4.4
Pharyngolaryngeal pain 14.1 1.1 20.7 0 9.9 0
Sepsis 12 5.4 7.6 6.5 4.4 4.4
Fluid overload 12 0 6.5 0 3.3 1.1
Increased alanine aminotransferase 10.9 3.3 27.2 4.3 17.6 2.2
Hyperphosphatemia 9.8 0 15.2 0 8.8 1.1

Hypersensitivity reactions occurred in 4.3% of Elitek-treated patients and 1.1% of Elitek/allopurinol-treated patients in Study 4. Clinical manifestations of hypersensitivity included arthralgia, injection site irritation, peripheral edema, and rash.

The following serious adverse reactions occurred at a difference in incidence of ≥2% in patients receiving Uricozyme compared to patients receiving allopurinol in randomized studies (Study 1 and Study 4): pulmonary hemorrhage, respiratory failure, supraventricular arrhythmias, ischemic coronary artery disorders, and abdominal and gastrointestinal infections.

The incidence of anaphylaxis, hemolysis, and methemoglobinemia was less than 1% of the 887 Elitek-treated patients entered on these clinical trials.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Uricozyme can elicit anti-product antibodies that bind to Uricozyme and in some instances inhibit the activity of Uricozyme in vitro [see Boxed Warning, Warnings and Precautions ].

In clinical trials of pediatric patients with hematologic malignancies, 24/218 patients tested (11%) developed antibodies by day 28 following Uricozyme administration as assessed by qualitative ELISA.

Using quasi-quantitative immunoassays in Uricozyme naïve adult patients with hematological malignancies, 47/260 (18%) patients were positive for anti-rasburicase immunoglobulin G (IgG), 21/260 (8%) patients were positive for anti-rasburicase neutralizing IgG, and 16/260 (6%) patients were positive for anti-rasburicase immunoglobulin E (IgE) from day 14 to 24 months after 5 daily doses of Uricozyme.

The incidence of antibody responses detected is highly dependent on the sensitivity and specificity of the assay, which have not been fully evaluated. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including serum sampling, timing and methodology, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Uricozyme with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because they are reported from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central nervous system disorders: convulsion, muscle contractions involuntary

Immune system disorders: Cases of anaphylaxis with potential fatal outcome have been reported.

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7 DRUG INTERACTIONS

Laboratory Test Interference

At room temperature, Uricozyme causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation.

Uric acid must be analyzed in plasma. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. Immediately immerse plasma samples for uric acid measurement in an ice water bath. Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection [see Boxed Warning ].

Uricozyme does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro. No metabolic-based drug interactions are therefore anticipated with these agents in patients.

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: May cause fetal harm. Use only if the potential benefit to the mother justifies the potential risk to the fetus.
  • Nursing Mothers: Discontinue nursing or Uricozyme taking into account the importance of the drug to the mother (8.3).

8.1 Pregnancy

Pregnancy Category C

There are no studies of Uricozyme in pregnant women. Reproductive toxicity studies in rabbits treated during organogenesis with approximately 10 to 100 times the recommended human dose of Uricozyme resulted in teratogenicity, including decreased fetal body weights and heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of Uricozyme. Other adverse effects were observed in rasburicase-treated pregnant rabbits at all dose levels tested and included pre and postimplantation losses, abortions, and decreased uterine weights [see Nonclinical Toxicology (13.2) ].

It is unknown whether Uricozyme can cross the placental barrier in humans and result in fetal harm. Because of the observed teratogenic effects of Uricozyme in animal reproductive studies, use Uricozyme during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Uricozyme is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Uricozyme, a decision should be made whether to discontinue nursing or to discontinue Uricozyme, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and efficacy of Uricozyme was studied in 246 pediatric patients ranging in age from 1 month to 17 years. There were insufficient numbers of patients between 0 and 6 months to determine whether they respond differently from older children. Mean uric acid AUC0–96 hr was higher in children <2 years of age (n=24; 150 ± s.e. 16 mg hr/dL) than those age 2 to 17 years (n=222; 108 ± s.e. 4 mg hr/dL). Children <2 years of age had a lower rate of achieving normal uric acid concentration by 48 hours (83% [95% CI: 62, 95]) than those 2 to 17 years (93% [95% CI: 89, 95]).

8.5 Geriatric Use

Of the total number of adults treated with Uricozyme (n=434) in clinical studies, 30% were aged 65 and over while 8% were aged 75 and over. No overall differences in pharmacokinetics, safety, and effectiveness were observed between the elderly and younger patients.

10 OVERDOSAGE

The maximum reported overdosage of Uricozyme is a single dose of 1.3 mg/kg. No adverse events occurred in reported cases of overdosage. Monitor patients who receive an overdose and initiate supportive measures if required.

11 DESCRIPTION

Uricozyme (rasburicase) is a recombinant urate-oxidase produced by a genetically modified Saccharomyces cerevisiae strain. The cDNA coding for Uricozyme was cloned from a strain of Aspergillus flavus.

Uricozyme is a tetrameric protein with identical subunits. Each subunit is made up of a single 301 amino acid polypeptide chain with a molecular mass of about 34 kDa. The drug product is a sterile, white to off-white, lyophilized powder intended for intravenous administration following reconstitution with a diluent. Uricozyme is supplied in 3 mL and 10 mL colorless, glass vials containing Uricozyme at a concentration of 1.5 mg/mL after reconstitution.

Uricozyme 1.5 mg presentation contains 1.5 mg Uricozyme, 10.6 mg mannitol, 15.9 mg L-alanine, between 12.6 and 14.3 mg of dibasic sodium phosphate (lyophilized powder), and a diluent (1 mL Water for Injection, USP, and 1 mg Poloxamer 188).

Uricozyme 7.5 mg presentation contains 7.5 mg of Uricozyme, 53 mg mannitol, 79.5 mg L-alanine, and between 63 and 71.5 mg dibasic sodium phosphate (lyophilized powder) and a diluent (5 mL Water for Injection, USP, and 5 mg Poloxamer 188).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

In humans, uric acid is the final step in the catabolic pathway of purines. Uricozyme catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite.

12.2 Pharmacodynamics

The measurement of plasma uric acid was used to evaluate the effectiveness of Uricozyme in clinical studies. Following administration of either 0.15 or 0.20 mg/kg Uricozyme daily for up to 5 days, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least 7 days. There was no evidence of a dose response effect on uric acid control for doses between 0.15 and 0.20 mg/kg Uricozyme.

In preclinical in vivo studies, Uricozyme did not affect the activity of isoenzymes CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A, suggesting no induction or inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended Uricozyme dose and dosing schedule

12.3 Pharmacokinetics

The pharmacokinetics of Uricozyme was evaluated in both pediatric and adult patients with leukemia, lymphoma or other hematological malignancies. Uricozyme exposure, as measured by AUC0–24 hr and Cmax, tended to increase with a dose range from 0.15 to 0.2 mg/kg. The mean terminal half-life was similar between pediatric and adult patients and ranged from 15.7 to 22.5 hours. The mean volume of distribution of Uricozyme ranged from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients, respectively. Minimal accumulation of Uricozyme (<1.3 fold) was observed between days 1 and 5 of dosing. In adults, age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of Uricozyme. A cross-study comparison revealed that after administration of Uricozyme at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=22).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in animals to evaluate tumorigenic potential of Uricozyme have not been performed. Uricozyme was not mutagenic in the Ames, unscheduled DNA synthesis, chromosome analysis, mouse lymphoma, and micronucleus tests.

Uricozyme did not affect reproductive performance or fertility in male or female rats at a dose 50-fold higher than the recommended human dose.

13.2 Reproductive and Developmental Toxicology

Pregnant rabbits dosed daily with 10 to 100 times the human dose of Uricozyme during the period of organogenesis (gestation day 6–19) exhibited teratogenic effects, clinical signs of maternal toxicity including weight loss and mortality, decreases in uterine weights and viable fetuses, and increased fetal resorptions, postimplantation losses and abortions. Teratogenic effects included multiple heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of Uricozyme. There are no data available regarding the level of Uricozyme exposure in the offspring.

14 CLINICAL STUDIES

14.1 Pediatrics

Uricozyme was administered in three studies to 265 patients with acute leukemia or non-Hodgkin's lymphoma. These clinical studies were largely limited to pediatric patients. Uricozyme was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Uricozyme was administered prior to and concurrent with anti-tumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69).

Study 1

Study 1 was a randomized, open-label, controlled study conducted at six institutions, in which 52 pediatric patients were randomized to receive either Uricozyme (n=27) or allopurinol (n=25). The dose of allopurinol varied according to local institutional practice. Uricozyme was administered as an intravenous infusion over 30 minutes once (n=26) or twice (n=1) daily at a dose of 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Initiation of dosing was permitted at any time between 4 to 48 hours before the start of anti-tumor therapy and could be continued for 5 to 7 days after initiation of anti-tumor therapy. Patients were stratified at randomization on the basis of underlying malignant disease (leukemia or lymphoma) and baseline serum or plasma uric acid levels (<8 mg/dL and ≥8 mg/dL). The primary study objective was to demonstrate a greater reduction in uric acid concentration over 96 hours (AUC0–96 hr) in the Uricozyme group as compared to the allopurinol group. Uric acid AUC0–96 hr was defined as the area under the curve for plasma uric acid levels (mg hr/dL), measured from the last value prior to the first dose of Uricozyme until 96 hours after that first dose. Plasma uric acid levels were used for all uric acid AUC0–96 hr calculations [see Warnings and Precautions (5.4) ].

The demographics of the two study arms (Elitek vs. allopurinol) were as follows: age <13 years (82% vs 76%), males (59% vs 72%), Caucasian (59% vs 72%), ECOG performance status 0 (89% vs 84%), and leukemia (74% vs 76%). The median interval, in hours, between initiation of Uricozyme and of anti-tumor treatment was 20 hours, with a range of 70 hours before to 10 hours after the initiation of anti-tumor treatment (n=24, data not reported for 3 patients).

The uric acid AUC0–96 hr was significantly lower in the Uricozyme group (128 ± s.e. 14 mg hr/dL) as compared to the allopurinol group (328 ± s.e. 26 mg hr/dL). All but one patient in the Uricozyme arm had reduction and maintenance of uric acid levels to within or below the normal range during the treatment. The incidence of renal dysfunction was similar in the two study arms; one patient in the allopurinol arm developed acute renal failure.

Study 2

Study 2 was a multi-institutional, single-arm study conducted in 89 pediatric and 18 adult patients with hematologic malignancies. Patients received Uricozyme at a dose of 0.15 mg/kg/day. The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours where maintenance of uric acid concentration was defined as: 1) achievement of uric acid concentration ≤6.5 mg/dL (patients <13 years) or ≤7.5 mg/dL (patients ≥13 years) within a designated time point (48 hours) from initiation of Uricozyme and maintained until 24 hours after the last administration of study drug; and 2) control of uric acid level without the need for allopurinol or other agents.

The study population demographics were: age <13 years (76%), males (61%), Caucasian (91%), ECOG performance status=0 (92%), and leukemia (89%).

The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 2 was 99% (106/107).

Study 3

Study 3 was a multi-institutional, single-arm study conducted in 130 pediatric patients and 1 adult patient with hematologic malignancies. Patients received Uricozyme at either a dose of 0.15 mg/kg/day (n=12) or 0.2 mg/kg/day (n=119). The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours as defined for Study 2 above.

The study population demographics were: age <13 years (76%), Caucasian (83%), males (67%), ECOG=0 (67%), and leukemia (88%).

The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 3 was 92% in the 0.15 mg/kg group (n=12) and 95% in the 0.2 mg/kg group (n=119).

Pooled Analyses of Studies 1, 2, and 3

Data from the 3 studies (n=265) were pooled and analyzed according to the plasma uric acid levels over time. The pre-treatment plasma uric acid concentration was ≥8 mg/dL in 61 patients and was <8 mg/dL in 200 patients. The median uric acid concentration at baseline, at 4 hours following the first dose of Uricozyme, and the per-patient fall in plasma uric acid concentration from baseline to 4 hours were calculated in those patients with both pre-treatment and 4-hour post-treatment values. Among patients with pre-treatment uric acid ≥8 mg/dL (baseline median 10.6 mg/dL [range 8.1–36.4]), the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 9.1 mg/dL (0.3–19.3 mg/dL). Among the patients with a pre-treatment plasma uric acid level <8 mg/dL (baseline median 4.6 mg/dL [range 0.2–7.9 mg/dL]), the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 4.1 mg/dL (0.1–7.6 mg/dL).

Figure 1 is a box and whisker plot of plasma uric acid levels inclusive of 261 of the 265 Uricozyme treated patients from Studies 1, 2, and 3. Of the 261 evaluable patients, plasma uric acid concentration was maintained [see Study 2 for the definition of uric acid concentration maintenance], by 4 hours for 92% of patients (240/261), by 24 hours for 93% of patients (245/261), by 48 hours for 97% of patients (254/261), by 72 hours for 99% of patients (260/261), and by 96 hours for 100% of patients (261/261). Of the subset of 61 patients whose plasma uric acid level was elevated at baseline (≥8 mg/dL), plasma uric acid concentration was maintained by 4 hours for 72% of patients (44/61), by 24 hours for 80% of patients (49/61), by 48 hours for 92% of patients (56/61), by 72 hours for 98% of patients (60/61), and by 96 hours for 100% (61/61).

Figure

14.2 Studies in Adults

A total of 342 adults with either leukemia, lymphoma, or other hematologic malignancy received Uricozyme in five studies (one randomized study, Study 4, and four uncontrolled studies). Across the five studies, Uricozyme was administered at a dose of 0.15 mg/kg/day (n=38) or 0.2 mg/kg/day (n=304).

Study 4 was a randomized (1:1:1), multi-center, open-label study conducted in patients with leukemia, lymphoma, and solid tumor malignancies at risk for hyperuricemia and TLS. A total of 275 adult patients received at least one dose of study drug. The median age was 56 years, 62% were males, 80% were Caucasian, 66% had leukemia, 29% had lymphoma; 18% were hyperuricemic (uric acid ≥7.5 mg/dL) at study entry. Patients in Arm A received Uricozyme for 5 days (n=92). Patients in Arm B received Uricozyme from day 1 through day 3 followed by oral allopurinol from day 3 through day 5 (overlap on day 3: Uricozyme and allopurinol administered approximately 12 hours apart) (n=92). Patients in Arm C received oral allopurinol for 5 days (n=91). Uricozyme was administered at the dose of 0.2 mg/kg/day as a 30-minute infusion once daily. Allopurinol was administered orally at the dose of 300 mg once a day. Patients were eligible for the study if they were either at high risk or potential risk for TLS. The major endpoint of this study was the uric acid response rate defined as the proportion of patients with plasma uric acid levels ≤7.5 mg/dL from day 3 to day 7, after initiation of antihyperuricemic treatment.

Table 2 presents the response rates in the three treatment arms. The response rate in arm A was significantly greater than in arm C (p=0.0009). The response rate was higher for arm B compared to arm C; this difference was not statistically significant.

Arm A

Uricozyme

n=92

Arm B

Uricozyme / Allopurinol

n=92

Arm C

Allopurinol

n=91

Response Rate % (95% CI) 87% (80%, 94%) 78% (70%, 87%) 66% (56%, 76%)
Non-Response Rate % 13% 22% 34%
Failed to control uric acid 0 0 11%
Hyperuricemic treatment extended beyond 5 days 0 6.5% 4.4%
Missing uric acid samples 13% 15% 19%

There were no patients with documented failure to control uric acid in arms A or B. In arm C, 34% of patients did not have a uric acid response; 11% due to failure to control uric acid and 4.4% due to the need for extended antihyperuricemic treatment.

Box and whisker plots of uric acid over time for the patient population (Figure 2) show that in the two arms containing Uricozyme, uric acid levels were ≤2 mg/dL in 96% of patients at 4 hours of the day 1 dose.

Figure 2. Uric Acid Concentration Over Time – Patient Population Box and Whisker Plot
Figure

Tumor Lysis Syndrome (TLS)

Clinical TLS was defined by changes in at least two or more laboratory parameters for hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia and at least one of the following events occurring within 7 days of treatment: renal failure/injury, need for renal dialysis, and/or serum creatinine increase >1.5 ULN, arrhythmia or seizure. Clinical TLS occurred in 3% of Elitek-treated patients, 3% of Elitek/allopurinol-treated patients, and 4% of allopurinol-treated patients.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

NDC 0024-5150-10: One carton contains 3 single-dose vials each containing 1.5 mg of Uricozyme and 3 ampules each containing 1 mL diluent.

NDC 0024-5151-75: One carton contains 1 single-dose vial containing 7.5 mg of Uricozyme and 1 ampule containing 5 mL diluent.

Storage and Handling

The lyophilized drug product and the diluent for reconstitution should be stored at 2–8°C (36–46°F). Do not freeze. Protect from light.

17 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions

Instruct patients to notify their physician immediately if any of the following occur: allergic reaction, bronchospasm, chest pain or tightness, dyspnea, hypoxia, hypotension, shock or urticaria [see Boxed Warning, Warnings and Precautions (5.1) ].

Manufactured by:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

U.S. License No. 1752

Revised: 09/2017

© 2017 sanofi-aventis U.S. LLC

PRINCIPAL DISPLAY PANEL - 1.5 mg Kit Carton

NDC 0024-5150-10

Uricozyme ®

Uricozyme

1.5 mg

Three single-use vials

Three diluent ampules

FOR INTRAVENOUS INFUSION

Sterile – Contains No Preservatives – Single Use Vials

Rx only

sanofi aventis

PRINCIPAL DISPLAY PANEL - 1.5 mg Kit Carton

PRINCIPAL DISPLAY PANEL - 7.5 mg Kit Carton

NDC 0024-5151-75

Uricozyme ®

Uricozyme

7.5 mg

One single-use vial

One diluent ampule

FOR INTRAVENOUS INFUSION

Sterile – Contains No Preservatives – Single Use Vial

Rx only

sanofi aventis

PRINCIPAL DISPLAY PANEL - 7.5 mg Kit Carton

Uricozyme pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Uricozyme available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Uricozyme destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Uricozyme Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Uricozyme pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ELITEK (RASBURICASE) KIT [SANOFI-AVENTIS U.S. LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "rasburicase". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  3. "Rasburicase - DrugBank". http://www.drugbank.ca/drugs/DB0004... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Uricozyme?

Depending on the reaction of the Uricozyme after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Uricozyme not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Uricozyme addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Uricozyme, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Uricozyme consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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