Drugs Details

Drugs Info of Krystexxa
Drugs Details
  • Drugs Type  : Multum
  • Date : 11th Feb 2015 02:50 am
  • Brand Name : Krystexxa
  • Generic Name : pegloticase (Pronunciation: peg LOE ti kase)
Descriptions

KRYSTEXXA (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to monomethoxypoly (ethylene glycol) [mPEG] (10 kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase subunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa.

KRYSTEXXA (pegloticase injection) is intended for intravenous infusion.

KRYSTEXXA is a sterile, clear, colorless solution containing 8 mg/mL pegloticase in phosphate-buffered saline.

KRYSTEXXA (pegloticase) concentrations are expressed as concentrations of uricase protein. Each mL of KRYSTEXXA (pegloticase injection) contains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen Phosphate Dihydrate (Na2HPO4•2H2O), 8.77 mg Sodium Chloride (NaGl), 0.43 mg Sodium Dihydrogen Phosphate Dihydrate (NaH2PO4•2H2O), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein).

What are the possible side effects of pegloticase (Krystexxa)?

Some people receiving a pegloticase injection have had a reaction to the infusion (when the medicine is injected into the vein). Infusion reactions may also occur after the injection is given. Tell your caregiver right away if you feel itchy, nervous, light-headed, short of breath, or have a fast heartbeat, chest discomfort, or redness of your skin during the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; wheezing, difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you...

Read All Potential Side Effects and See Pictures of Krystexxa »

What are the precautions when taking pegloticase injection (Krystexxa)?

Before receiving pegloticase, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: a certain metabolic disorder (G6PD deficiency), favism, heart failure.

If you are of African or Mediterranean descent, you may be at higher risk for G6PD deficiency and should be tested to see if you have this condition before starting this medication.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal...

Read All Potential Precautions of Krystexxa »

This monograph has been modified to include the generic and brand name in many instances.

Indications

KRYSTEXXA™ (pegloticase) is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy.

Gout refractory to conventional therapy occurs in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose or for whom these drugs are contraindicated.

Important Limitations of Use

KRYSTEXXA (pegloticase injection) is not recommended for the treatment of asymptomatic hyperuricemia.

Dosage Administration

Dosage

The recommended dose and regimen of KRYSTEXXA (pegloticase injection) for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks.

The optimal treatment duration with KRYSTEXXA (pegloticase injection) has not been established.

Preparation

Visually inspect KRYSTEXXA (pegloticase injection) for particulate matter and discoloration before administration, whenever solution and container permit. Do not use vials if either is present [see Dosage Forms and Strengths]

Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA (pegloticase injection) from the vial into a sterile syringe. Discard any unused portion of product remaining in the 2 mL vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs.

Invert the infusion bag containing the dilute KRYSTEXXA (pegloticase injection) solution a number of times to ensure thorough mixing. Do not shake.

KRYSTEXXA (pegloticase injection) diluted in infusion bags is stable for 4 hours at 2° to 8°C (36° to 46°F) and at room temperature (20° to 25°C, 68° to 77°F). However it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution. [see HOW SUPPLIED]

Before administration, allow the diluted solution of KRYSTEXXA (pegloticase injection) to reach room temperature. KRYSTEXXA (pegloticase injection) in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave).

Administration

Do not administer as an intravenous push or bolus.

Monitoring Therapy: The risk of anaphylaxis and infusion reactions is higher in patients who have lost therapeutic response. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. [see WARNINGS AND PRECAUTIONS]

The KRYSTEXXA (pegloticase injection) admixture should only be administered by intravenous infusion over no less than 120 minutes via gravity feed, syringe-type pump, or infusion pump.

Patients should receive pre-infusion medications (e.g. antihistamines, corticosteroids), to minimize the risk of anaphylaxis and infusion reactions. Administer KRYSTEXXA (pegloticase injection) in a healthcare setting and by healthcare providers prepared to manage anaphylaxis and infusion reactions, and observe patients for an appropriate period of time after administration, [see WARNINGS AND PRECAUTIONS]

If an infusion reaction occurs during the administration of KRYSTEXXA (pegloticase injection) , the infusion may be slowed, or stopped and restarted at a slower rate, at the discretion of the physician. Since infusion reactions can occur after completion of infusion, observation of patients for approximately an hour post-infusion should be considered, [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

How Supplied

Dosage Forms And Strengths

KRYSTEXXA is a clear, colorless, sterile 8 mg/mL solution of pegloticase in a 2 mL single-use vial, expressed as amounts of uricase protein. KRYSTEXXA (pegloticase injection) must be diluted prior to use.

How Supplied

KRYSTEXXA (pegloticase injection) is supplied as a clear, colorless, sterile solution in phosphate buffered saline intended for intravenous infusion after dilution. KRYSTEXXA (pegloticase injection) is supplied in a single-use 2 mL glass vial with a Teflon® coated (latex-free) rubber injection stopper to deliver KRYSTEXXA (pegloticase injection) as 8 mg of uricase protein in 1 mL volume.

Storage and Handling

Before the preparation for use, KRYSTEXXA (pegloticase injection) must be stored in the carton and maintained at all times under refrigeration between 2° to 8°C (36° to 46°F). Protect from light. Do not shake or freeze.

Do not use beyond the expiration date stamped.

NDC# 54396-801-01

Manufactured by: Savient Pharmaceuticals, Inc. One Tower Center, 14th Floor East Brunswick, NJ 08816. Issued September 2010

This monograph has been modified to include the generic and brand name in many instances.

Side Effects

The most commonly reported serious adverse reactions from pre-marketing controlled clinical trials were anaphylaxis, which occurred at a frequency of 6.5% in patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, compared to none with placebo; infusion reactions, which occurred at a frequency of 26% in patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, compared to 5% treated with placebo; and gout flares, which were more common during the first 3 months of treatment with KRYSTEXXA (pegloticase injection) compared with placebo. All patients in pre-marketing controlled clinical trials were pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen to prevent anaphylaxis and infusion reaction. Patients also received non-steroidal anti-inflammatory drugs or colchicine, or both, for at least 7 days as gout flare prophylaxis before beginning KRYSTEXXA treatment, [see Boxed Warning, WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

The data described below reflect exposure to KRYSTEXXA (pegloticase injection) in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 6-month clinical trials: 85 patients were treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks; 84 patients were treated with KRYSTEXXA (pegloticase injection) 8 mg every 4 weeks; and 43 patients were treated with placebo. These patients were between the ages of 23 and 89 years (average 55 years); 173 patients were male and 39 were female; and 143 patients were White/Caucasian, 27 were Black/African American, 24 were Hispanic/Latino and 18 were all other ethnicities. Common co-morbid conditions among the enrolled patients included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%) arrhythmia(16%) and cardiac failure/left ventrieute dysfunction (12%).

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.

Anaphylaxis

Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA (pegloticase injection) or placebo injection with no other identifiable cause. Using these clinical criteria, anaphylaxis was identified in 14 (5.1%) of 273 total patients studied in the clinical program of IV KRYSTEXXA (pegloticase injection) . The frequency was 6.5% for the every 2-week dosing regimen (8 of 123 patients), and 4.8% for the 4-week dosing frequency (6 of 126) of KRYSTEXXA (pegloticase injection) . There were no cases of anaphylaxis in patients receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment. This occurred with patients being pre-treated with an oral antihistamine, intravenous corticosteroid, and acetaminophen, [see Boxed Warning, WARNINGS AND PRECAUTIONS]

Infusion Reactions

Infusion reactions occurred in 26% of patients in the 2 week dosing regimen group and 41% of patients in the 4 week dosing regimen group^ compared to 5% of placebo-treated patients. Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion^ and approximately 91% occurred during the time of infusion. Some infusion reaction manifestations were reduced with slowing the rate of infusion, or stopping the infusion and restarting the infusion at a slower rate. These infusion reactions occurred with all patients being pre-treated with an oral antihistamine, intravenous corticosteroid and acetaminophen. [see Boxed Warning, WARNINGS AND PRECAUTIONS]

Gout Flares

Gout flares were common in the study patients before randomization to treatment, with patients experiencing an average of 10 flares in the preceding 18 months prior to study entry. During the controlled treatment period with KRYSTEXXA (pegloticase injection) or placebo, the frequencies of gout flares were high in all treatment groups, but more so with KRYSTEXXA (pegloticase injection) treatment during the first 3 months of treatment, which seemed to decrease in the subsequent 3 months of treatment. The percentages of patients with any flare for the first 3 months were 74%, 81 %, and 51 %, for KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, KRYSTEXXA (pegloticase injection) 8 mg every 4 weeks, and placebo, respectively. The percentages of patients with any flare for the subsequent 3 months were 41%, 57% and 67%, for KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, KRYSTEXXA (pegloticase injection) 8 mg every 4 weeks, and placebo, respectively. Patients received gout flare prophylaxis with colchicine and/or nonsteroidal anti-inflammatory drugs (NS AIDs) starting at least one week before receiving KRYSTEXXA. [see WARNINGS AND PRECAUTIONS]

Congestive Heart Failure

Two cases of congestive heart failure exacerbation occurred during the trials in patients receiving treatment with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks. No cases were reported in placebo-treated patients. Four subjects had exacerbations of pre-existing congestive heart failure while receiving KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks during the open-label extension study, [see WARNINGS AND PRECAUTIONS].

Other Adverse Reactions

The most commonly reported adverse reactions that occurred in greater than or equal to 5% of patients treated with KRYSTEXXA (pegloticase injection) 8mg every 2 weeks are provided in Table I.

Table 1. Adverse Reactions Occurring in 5% or More of Patients Treated with KRYSTEXXA (pegloticase injection) Compared to Placebo

Adverse Reaction
(Preferred Term)
KRYSTEXXA (pegloticase injection)
8 mg every 2 weeks
(N-85)
Na (%)
Placebo
(N=43)
N (%)
Gout flare 65(77%) . 35 (81%)
Infusion reaction 22 (26%) 2(5%)
Nausea 10(12%) 1 (2%)
Contusionb or Ecchymosisb 9(11%) 2 (5%)
Nasopharyngitis 6(7%). 1(2%)
Constipation 5 (6%) 2 (5%)
Chest Pain 5(6%) 1 (2%)
Anaphylaxis 4 (5%) 0 (0%)
Vomiting 4 (5%) 1 (2%)
a If the same subject in a given group had more than one occurrence in the same preferred term event category, the subject was counted only once.
b Most did not occur on the day of infusion and could be related to other factors (e.g. concomitant medications relevant to contusion or ecchymosis, insulin dependent diabetes mellitus).

Immunogenicity

Anti-pegloticase antibodies developed in 92% of patients treated with KRYSTEXXA (pegloticase injection) every 2 weeks, and 28% for placebo. Anti-PEG antibodies were also detected in 42% of patients treated with KRYSTEXXA. High anti-pegloticase antibody titer was associated with a failure to maintain pegloticase-induced normalization of uric acid. The impact of anti-PEG antibodies on patients' responses to other PEG-containing therapeutics is unknown.

There was a higher incidence of infusion reactions in patients with high anti-pegloticase antibody titer: 53% (16 of 30) in the KRYSTEXXA (pegloticase injection) every 2 weeks group compared to 6% in patients who had undetectable or low antibody titers.

As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity and assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the comparison of the incidence of antibodies to pegloticase with the incidence of antibodies to other products may be misleading.

Read the Krystexxa (pegloticase injection) Side Effects Center for a complete guide to possible side effects

Learn More »

Interactions

No studies of interactions of KRYSTEXXA with other drugs have been conducted. Because anti-pegloticase antibodies appear to bind to the PEG portion of the drug, there may be potential for binding with other PEGylated products. The impact of anti-PEG antibodies on patients' responses to other PEG-containing therapeutics is unknown.

Read the Krystexxa Drug Interactions Center for a complete guide to possible interactions

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This monograph has been modified to include the generic and brand name in many instances.

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Anaphylaxis

During pre-marketing controlled clinical trials, anaphylaxis was reported with a frequency of 6.5% of patients treated with KRYSTEXXA (pegloticase injection) every 2 weeks, compared to none with placebo. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate. [See ADVERSE REACTIONS]

KRYSTEXXA (pegloticase injection) should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids, Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA (pegloticase injection) . Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting.

The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL.

Infusion Reactions

During pre-marketing controlled clinical trials, infusion reactions were reported in 26% of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, and 41% of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 4 weeks, compared to 5% of patients treated with placebo. These infusion reactions occurred in patients being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate. [See ADVERSE REACTIONS]

KRYSTEXXA (pegloticase injection) should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA (pegloticase injection) should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate.

The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL.

Gout Flares

Gout flares may occur after initiation of KRYSTEXXA. [see ADVERSE REACTIONS] An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA (pegloticase injection) therapy and lasting at least 6 months, unless medically contraindicated or not tolerated. KRYSTEXXA (pegloticase injection) does not need to be discontinued because of a gout flare. The gout flare should be managed concurrently as appropriate for the individual patient, [see DOSAGE AND ADMINISTRATION]

Congestive Heart Failure

KRYSTEXXA (pegloticase injection) has not been formally studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation, [see ADVERSE REACTIONS] Exercise caution when using KRYSTEXXA (pegloticase injection) in patients who have congestive heart failure and monitor patients closely following infusion.

Re-treatment with KRYSTEXXA (pegloticase injection)

No controlled trial data are available on the safety and efficacy of re-treatment with KRYSTEXXA (pegloticase injection) after stopping treatment for longer than 4 weeks. Due to the immunogenicity of KRYSTEXXA (pegloticase injection) , patients receiving re-treatment may be at increased risk of anaphylaxis and infusion reactions. Therefore, patients receiving re-treatment after a drug-free interval should be monitored carefully, [see ADVERSE REACTIONS]

Patient Counseling Information

See Medication Guide

General Information

Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment.

Anaphylaxis and Infusion Reactions

  • Anaphylaxis and infusion reactions can occur at any infusion while on therapy. Counsel patients on the importance of adhering to any prescribed medications to help prevent or lessen the severity of these reactions.
  • Educate patients on the signs and symptoms of anaphylaxis, including wheezing, peri-oral or lingual edema, hemodynamic instability, and rash or urticaria.
  • Educate patients on the most common signs and symptoms of an infusion reaction, including urticaria (skin rash), erythema (redness of the skin), dyspnea (difficulty breathing), flushing, chest discomfort, chest pain, and rash.
  • Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after the infusion of KRYSTEXXA. [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency

Inform patients not to take KRYSTEXXA (pegloticase injection) if they have a condition known as G6PD deficiency. Explain to patients that G6PD deficiency is more frequently found in individuals of African or Mediterranean ancestry land that they may be tested to determine if they have G6PD deficiency, unless already known. [See CONTRAINDICATIONS]

Gout Flares

Explain to patients that gout flares may initially increase when starting treatment with KRYSTEXXA (pegloticase injection) , and that medications to help reduce flares may need to be taken regularly for the first few months after KRYSTEXXA (pegloticase injection) is started, [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS] Advise patients that they should not stop KRYSTEXXA (pegloticase injection) therapy if they have a flare.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of pegloticase.

The genotoxic potential of pegloticase has not been evaluated. Fertility studies in animals have not been performed.

Animal Toxicology and/or Pharmacology

In a 12-week intravenous repeat-dose study in dogs, there was a dose-dependent increase in vacuolated macrophages in the spleen. The presence of vacuolated macrophages likely reflects accumulated removal of injected pegloticase (foreign) material from the circulation. There was no evidence of degeneration, inflammation, or necrosis associated with the vacuoles findings, however there was evidence of decreased functional response to liposaccharides.

In a 39-week, repeat dose dog study, there was a dose dependent increase in vacuolated cells in several organs, including the spleen, adrenal gland , liver, heart, duodenum and jejunum. In the spleen, liver, duodenum and jejunum, these vacuoles were within macrophages and most likely represented phagocytic removal of pegloticase from the circulation. However, the vacuolated cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of the heart, vacuoles were in the cytoplasm of endothelial cells in the intimal lining of the aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and zona fasciculata. The clinical significance of these findings and the functional consequences are unknown.

Use In Specific Populations

Pregnancy

Pregnancy Category C

A complete evaluation of the reproductive and developmental toxicity of pegloticase has not been completed. Adequate animal reproduction studies have not been conducted with KRYSTEXXA (pegloticase injection) . It is not known whether KRYSTEXXA (pegloticase injection) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies in pregnant women, KRYSTEXXA (pegloticase injection) should be used during pregnancy only if clearly needed.

Pegloticase was not teratogenic in rats administered 0, 5,10, or 40 mg/kg twice weekly by the intravenous route on gestation days 6 through 16 (the doses are approximately 6-fold to 50-fold higher than the maximum recommended human dose (MRHD) of 8 mg (0.133 mg/kg (based on a 60 kg person) every 2 weeks based on a mg/m2 comparison).

Nursing Mothers

It is not known whether this drug 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, it is not recommended to administer KRYSTEXXA (pegloticase injection) to a nursing mother.

Pediatric Use

The safety and effectiveness of KRYSTEXXA (pegloticase injection) in pediatric patients less than 18 years of age have not been established.

Geriatric Use

Of the total number of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks in the controlled studies, 34% (29 of 85) were 65 years of age and older and 12% (10 of 85) were 75 years of age and older. No overall differences in safety or effectiveness were observed between older and younger patients, but greater sensitivity of some older individual cannot be ruled out. No dose adjustment is needed for patients 65 years of age and older.

Renal Impairment

No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks had a creatinine clearance of ≤ 62.5 mL/min. No overall differences in efficacy were observed.

This monograph has been modified to include the generic and brand name in many instances.

OverDose

No reports of overdosage with KRYSTEXXA (pegloticase injection) have been reported. The maximum dose that has been administered as a single intravenous dose is 12 mg as uricase protein.

Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote has been identified.

ContrainDications

Glucose-6-phosphate dehydrogenase (G6PD) deficiency: KRYSTEXXA (pegloticase injection) is contraindicated in patients with G6PD deficiency due to the risk of hemolysis and methemoglobinemia. It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened for G6PD deficiency before starting KRYSTEXXA (pegloticase injection) .

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism of Action

KRYSTEXXA (pegloticase injection) is a uric acid specific enzyme which is a recombinant uricase and achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water soluble purine metabolite. It is readily eliminated, primarily by renal excretion.

Pharmacodynamics

Approximately 24 hours following the first dose of KRYSTEXXA (pegloticase injection) , mean plasma uric acid levels for subjects in the KRYSTEXXA (pegloticase injection) groups were 0.7 mg/dL for the KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2 mg/dL.

In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12 mg of pegloticase in 24 patients with symptomatic gout (n=4 subjects/dose group), plasma uric acid decreased with increasing pegloticase dose or concentrations. The duration of suppression of plasma uric acid appeared to be positively associated with pegloticase dose. Sustained decrease in plasma uric acid below the solubility concentration of 6 mg/dL for more than 300 hours was observed with doses of 8 mg and 12 mg.

Pharmacokinetics

Pegloticase levels were determined in serum based on measurements of uricase enzyme activity.

Following single intravenous infusions of 0.5 mg to 12 mg pegloticase in 23 patients with symptomatic gout, maximum serum concentrations of pegloticase increased in proportion to the dose administered.

The population pharrnacokinetic analysis showed that age, sex, weight, and creatinine clearance did not influence the pharmacokinetics of pegloticase. Significant covariates included in the model for determining clearance and volume of distribution were found to be body surface area and anti-pegloticase antibodies.

The pharmacokinetics of pegloticase has not been studied in children and adolescents.

No formal studies were conducted to examine the effects of either renal or hepatic impairment on pegloticase pharmacokinetics.

Clinical Studies

The efficacy of KRYSTEXXA (pegloticase injection) was studied in adult patients with chronic gout refractory to conventional therapy in two replicate, multicenter, randomized, double-blind, placebo-controlled studies of six months duration: Trial 1 and Trial 2. Patients were randomized to receive KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio. Studies were stratified for the presence of tophi. Seventy-one percent (71%) of patients had baseline tophi. All patients were prophylaxed with an oral antihistamine, intravenous corticosteroid and acetaminophen. Patients also received prophylaxis for gout flares with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine, or both, beginning at least one week before KRYSTEXXA (pegloticase injection) treatment unless medically contraindicated or not tolerated. Patients who completed the randomized clinical trials were eligible to enroll in a 2-year open label extension study.

Entry criteria for patients to be eligible for the trials were: baseline serum uric acid (SUA) of at least 8 mg/dL; had symptomatic gout with at least 3 gout flares in the previous 18 months or at least 1 gout tophus or gouty arthritis; and had a self-reported medical contraindication to allopurinol or medical history of failure to normalize uric acid (to less than 6 mg/dL) with at least 3 months of allopurinol treatment at the maximum medically appropriate dose.

The mean age of study subjects was 55 years (23-89); 82% were male, mean body mass index (BMI) was 33 kg/m2, mean duration of gout was 15 years, and mean baseline SUA was 10 mg/dL.

To assess the efficacy of KRYSTEXXA (pegloticase injection) in lowering uric acid, the primary endpoint in both trials was the proportion of patients who achieved plasma uric acid (PUA) less than 6 mg/dL for at least 80% of the time during Month 3 and Month 6. As shown in Table 2, a greater proportion of patients treated with KRYSTEXXA (pegloticase injection) every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. Although the 4 week regimen also1 demonstrated efficacy for the primary endpoint, this regimen was associated with increased frequency of anaphylaxis and infusion reactions and less efficacy with respect to tophi.

Table 2: Plasma Uric Acid < 6 mg/dL for at Least 80% of the Time During Months 3 and 6

Treatment Group N Number (%) of Subjects Who Met Response Criteria 95% Confidence Interval1 P-Value2
Trial 1
  Pegloticase 8 mg every 2 weeks 43 7.0 (47%) [32%. 61%] O.001
  Pegloticase 8 mg every 4 weeks 41 8 (20%) [7%, 32%] 0.044
  Placebo 20 0(0%).    
Trial 2
  Pegloticase 8 mg every 2 weeks 42 16(38%) [23%, 53%] O.001
  Pegloticase 8 mg every 4 weeks 43 21(49%). [34%, 64%] < 0.001
  Placebo 23 0 (0%)    
1 95% confidence interval for differences in responder rate between pegloticase group vs. placebo
2 P-value using Fisher's exact test to compare pegloticase group vs. placebo

Note: Based on post-hoc analyses of the clinical trial data, if KRYSTEXXA (pegloticase injection) had been stopped when a patient's uric acid level rose to greater than 6 mg/dL on a single occasion, the incidence of infusion reactions would have been reduced by approximately 67%, but the success rates for the primary efficacy endpoint would have been reduced by approximately 20%. If KRYSTEXXA (pegloticase injection) had been stopped after 2 consecutive uric acid levels greater than 6 mg/dL, the incidence of infusion reactions would have been half, and there would have been little change in the efficacy outcome.

The effect of treatment on tophi was a secondary efficacy endpoint and was assessed using standardized digital photography, image analysis, and a Central Reader blinded to treatment assignment. Approximately 70% of patients had tophi at baseline. A pooled analysis of data from Trial 1 and Trial 2 was performed as pre-specified in the protocols. At Month 6, the percentage of patients who achieved a complete response (defined as 100% resolution of at least one target tophus, no new tophi appear and no single tophus showing progression) was 45%, 26%, and 8%, with KRYSTEXXA (pegloticase injection) 8 mg every 2 weeks, KRYSTEXXA (pegloticase injection) 8 mg every 4 weeks, and placebo, respectively. The difference between KRYSTEXXA (pegloticase injection) and placebo was statistically significant for the every 2 week dosing regimen, but not for the every 4 week dosing regimen.

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

Medication Guide

KRYSTEXXA®
(Kris-TEX-a)
(pegloticase) Injection for Intravenous Infusion

Read this Medication Guide before you start receiving KRYSTEXXA and before each treatment. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about your treatment with KRYSTEXXA.

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

Serious allergic reactions may happen in some people who receive KRYSTEXXA. These allergic reactions can be life threatening and usually happen within 2 hours of the infusion.

KRYSTEXXA should be given to you by a doctor or nurse in a healthcare setting where serious allergic reactions can be treated. Your doctor or nurse should watch you for any signs of a serious allergic reaction during and after your treatment with KRYSTEXXA.

Tell your doctor or nurse right away if you have any of these symptoms during or after your treatment with KRYSTEXXA:

  • wheezing, shortness of breath, cough, chest tightness, chest pain, or trouble breathing
  • dizziness, fainting, fast or weak heartbeat or feeling nervous
  • reddening of the face, itching, hives, or feeling warm
  • swelling of the throat or tongue, throat tightness, hoarse voice or trouble swallowing

What is KRYSTEXXA?

KRYSTEXXA is a prescription medicine used in adults to help reduce the signs and symptoms of gout that are not controlled by other treatments.

People with gout have too much uric acid in their bodies. Uric acid crystals collect in joints, kidneys, and other organs. This may cause pain, redness and swelling (inflammation). KRYSTEXXA works to lower blood levels of uric acid.

It is not known if KRYSTEXXA is safe and effective in children.

Who should not receive KRYSTEXXA?

Do not receive KRYSTEXXA if you have a rare blood problem called glucose 6phosphate dehydrogenase (G6PD) deficiency or favism. Your doctor may test you for G6PD before you start KRYSTEXXA.

What should I tell my doctor before receiving treatment with KRYSTEXXA?

Before you receive KRYSTEXXA, tell your doctor if you:

  • know you have G6PD deficiency
  • ever had any heart problems or high blood pressure
  • are pregnant or plan to become pregnant. It is not known if KRYSTEXXA will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
  • are breastfeeding or plan to breastfeed. It is not known if KRYSTEXXA passes into your breast milk. You and your doctor should decide if you will receive KRYSTEXXA or breastfeed.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Do not take any other uric acid lowering drug, such as allopurinol or febuxostat (Uloric®), while taking KRYSTEXXA.

Know the medicines you take. Keep a list of your medicines and show them to your doctor and pharmacist when you get a new medicine.

How will I receive KRYSTEXXA?

  • Your doctor may give you medicine before your treatment of KRYSTEXXA to help reduce your chance of getting a reaction. Take these medicines as directed by your doctor or nurse.
  • You will receive KRYSTEXXA through a needle in your vein (i.v. infusion).
  • Your treatment will take about 2 hours or sometimes longer. A doctor or nurse will give you the treatment.
  • You will receive KRYSTEXXA every 2 weeks.
  • If you have side effects, your doctor may stop or slow the infusion and may give you medicine to help the side effects.
  • A doctor or nurse will watch you for side effects while you receive KRYSTEXXA and for some time afterwards.
  • Your doctor may stop your KRYSTEXXA if your uric acid levels do not become normal and stay controlled or you have certain side effects.
  • Your gout flares may increase in the first 3 months when you start receiving KRYSTEXXA. Do not stop receiving KRYSTEXXA even if you have a flare as the amount of flares will decrease after 3 months of treatment. Your doctor may give you other medicines to help reduce your gout flares for the first few months after starting KRYSTEXXA.

What are the possible side effects of KRYSTEXXA?

KRYSTEXXA may cause serious side effects. See “What is the most important information I should know about KRYSTEXXA?”

The most common side effects of KRYSTEXXA include:

  • gout flares
  • allergic reactions. See “What is the most important information I should know about KRYSTEXXA.”
  • bruising
  • sore throat
  • constipation
  • chest pain
  • vomiting

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the side effects of KRYSTEXXA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Savient Pharmaceuticals at 1-888-579-7839.

General information about the safe and effective use of KRYSTEXXA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about KRYSTEXXA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about KRYSTEXXA that is written for health professionals.

For more information, go to www.KRYSTEXXA.com or www.SAVIENT.com or call 1-888-579-7839.

What are the ingredients in KRYSTEXXA?

Active ingredient: pegloticase

Inactive ingredients: disodium hydrogen phosphate dihydrate, sodium chloride, sodium dihydrogen phosphate dihydrate, and water for injection.

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

PEGLOTICASE - INJECTION

 

(peg-LOE-ti-kase)

 

COMMON BRAND NAME(S): Krystexxa

 

WARNING: Pegloticase may infrequently cause a serious allergic reaction. This may occur during or after the infusion of the medication. Your doctor will check your blood before each treatment and monitor you closely during and after infusion. Your doctor should prescribe other medications (such as antihistamines, corticosteroids) to help prevent an allergic reaction. However, serious allergic reactions may still occur in a few patients. Get medical help right away if you develop any signs of an allergic reaction, such as rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing, chest discomfort/pain.

 

USES: Pegloticase is used to treat gout which has not responded to the usual treatments. It works by lowering high levels of uric acid in your body. Increased uric acid in your body can cause gout.

 

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using pegloticase and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

If you are taking other medications (such as allopurinol, febuxostat) by mouth to lower the level of uric acid in your body, your doctor will direct you to stop the medication before starting and during treatment with pegloticase. Taking these drugs with pegloticase may lessen how well it works.

This medication is given by injection into a vein (over at least 2 hours) by a healthcare professional. It is usually given every 2 weeks.

Use this medication regularly in order to get the most benefit from it. Remember to receive it every 2 weeks. It may help to mark your calendar with a reminder.

You may experience more gout attacks for several months after starting this medicine while your body removes extra uric acid. Your doctor may prescribe additional medication (such as colchicine, nonsteroidal anti-inflammatory drugs-NSAIDs) to help prevent and treat these gout attacks.

Tell your doctor if your condition persists or worsens.

Consumer Overview Side Effect

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, sore throat, or runny nose may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Krystexxa (pegloticase injection) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: Before receiving pegloticase, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: a certain metabolic disorder (G6PD deficiency), favism, heart failure.

If you are of African or Mediterranean descent, you may be at higher risk for G6PD deficiency and should be tested to see if you have this condition before starting this medication.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Do not take other medications (such as allopurinol, febuxostat) taken by mouth to lower the level of uric acid in your body before and during treatment with pegloticase. (See also How to Use section.)

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

 

NOTES: Laboratory and/or medical tests (such as uric acid levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: For the best possible benefit, it is important to receive each dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

 

STORAGE: Not applicable. This medication is given in a hospital or clinic and will not be stored at home.

 

Information last revised March 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Krystexxa

Generic Name: pegloticase (Pronunciation: peg LOE ti kase)

  • What is pegloticase (Krystexxa)?
  • What are the possible side effects of pegloticase (Krystexxa)?
  • What is the most important information I should know about pegloticase (Krystexxa)?
  • What should I discuss with my healthcare provider before taking pegloticase (Krystexxa)?
  • How should I take pegloticase (Krystexxa)?
  • What happens if I miss a dose (Krystexxa)?
  • What happens if I overdose (Krystexxa)?
  • What should I avoid while taking pegloticase (Krystexxa)?
  • What other drugs will affect pegloticase (Krystexxa)?
  • Where can I get more information?

What is pegloticase (Krystexxa)?

Pegloticase is an enzyme that metabolizes uric acid into a harmless chemical that is eliminated from the body in urine.

Pegloticase is used to treat chronic gout. Pegloticase is usually given after other gout medications have been tried without successful treatment of symptoms.

Pegloticase may also be used for purposes not listed in this medication guide.

What are the possible side effects of pegloticase (Krystexxa)?

Some people receiving a pegloticase injection have had a reaction to the infusion (when the medicine is injected into the vein). Infusion reactions may also occur after the injection is given. Tell your caregiver right away if you feel itchy, nervous, light-headed, short of breath, or have a fast heartbeat, chest discomfort, or redness of your skin during the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; wheezing, difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • chest pain; or
  • flushing (warmth, redness, or tingly feeling).

Less serious side effects may include:

  • new gout flares;
  • nausea, vomiting, constipation;
  • easy bruising; or
  • stuffy nose, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Krystexxa (pegloticase injection) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about pegloticase (Krystexxa)?

You should not receive pegloticase if you are allergic to it, or if you have a genetic enzyme deficiency called glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Some drugs can interact with pegloticase and should not be used at the same time, especially allopurinol (Zyloprim), probenecid (Benemid), or febuxostat (Uloric).

To make sure pegloticase is safe for you, tell your doctor if you have gout, congestive heart failure, other heart problems, or high blood pressure.

You may be given other medications to prevent certain side effects of pegloticase. You may need to start taking these medications at least a week before you receive your pegloticase injection. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Tell your caregiver right away if you feel itchy, nervous, light-headed, short of breath, or have a fast heartbeat, chest discomfort, or redness of your skin when the medicine is injected into your vein.

Side Effects Centers
  • Krystexxa

Patient Detailed How Take

What should I discuss with my healthcare provider before taking pegloticase (Krystexxa)?

You should not receive pegloticase if you are allergic to it, or if you have a genetic enzyme deficiency called glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Some drugs can interact with pegloticase and should not be used at the same time. Tell your doctor about all other medications you use, especially:

  • allopurinol (Zyloprim);
  • probenecid (Benemid); or
  • febuxostat (Uloric).

To make sure pegloticase is safe for you, tell your doctor about your other medical conditions, especially:

  • gout;
  • congestive heart failure;
  • other heart problems; or
  • high blood pressure.

FDA pregnancy category C. It is not known whether pegloticase will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether pegloticase passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using pegloticase.

How should I take pegloticase (Krystexxa)?

Pegloticase is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Pegloticase must be given slowly, and the IV infusion can take at least 2 hours to complete.

You may be given other medications to prevent certain side effects of pegloticase. You may need to start taking these medications at least a week before you receive your pegloticase injection. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Pegloticase is usually given once every 2 weeks. Follow your doctor's dosing instructions very carefully.

When you first start using pegloticase, you may have an increase in gout flares. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 3 months of treatment.

Your doctor may recommend other gout medications during the first 6 months of your treatment with pegloticase.

To be sure this medication is helping your condition, your blood may need to be tested often. This will help your doctor determine how long to treat you with pegloticase. Visit your doctor regularly.

Side Effects Centers
  • Krystexxa

Patient Detailed Avoid Taking

What happens if I miss a dose (Krystexxa)?

Call your doctor for instructions if you miss an appointment for your pegloticase injection.

What happens if I overdose (Krystexxa)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking pegloticase (Krystexxa)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

What other drugs will affect pegloticase (Krystexxa)?

There may be other drugs that can interact with pegloticase. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist can provide more information about pegloticase.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 2.01. Revision date: 9/10/2012.

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