Krystexxa

Dosage Forms & Strengths

injectable solution

• 8mg/mL

Gout

Indicated for treatment of chronic gout in adult patients refractory to conventional treatment

8 mg IV infusion q2wk (see Administration)

<18 years: Safety and efficacy not established

Black Box Warnings

Anaphylaxis and infusion reactions have been reported; these reactions may occur with any infusion, including the first, and typically manifest within 2 h of infusion (although delayed-type hypersensitivity has also been reported)

Only administer in a healthcare setting, and monitor for appropriate period following infusion

Premedicate with antihistamines and corticosteroids

Risk for anaphylaxis is higher if serum uric acid level >6 mg/dL, monitor serum uric acid levels before infusion and consider discontinuing if levels increase to >6 mg/dL (particularly if 2 consecutive levels of >6 mg/dL are observed)

Do not administer to patients with history of G6PD Deficiency; Screen patients at risk for G6PD Deficiency prior to initiating therapy; Life threatening hemolytic reactions and methemoglobinemia have been reported in these patients

Contraindications

Hypersensitivity

G6PD-deficiency (increased risk of hemolysis and methemoglobinemia)

Cautions

Gout flare frequently observed (initiate gout flare prophylaxis with NSAID or colchicine at least 1 wk before starting pegloticase); gout flare prophylaxis recommended for at least first 6 months

Screen patients at higher risk of G6PD deficiency, especially those of African and Mediterranean ancestry

Caution with congestive heart failure (not formally studied in patients with CHF); congestive heart failure exacerbation may occur; monitor patients closely following infusion

Unknown if retreatment after stopping for longer than 4 wk increases risk of anaphylaxis, infusion reactions, or immunogenicity

Risk of infusion reaction is increased in patients whose uric acid is >6 mg/dL; if less than severe infusion reactions occur, may slow infusion or infusion stopped and restarted at lower rate at physician's discretion

Discontinue use of oral antihyperuricemic agents prior to therapy; do not initiate during course of therapy; agents may delay interpretation of ineffective pegloticase treatment

Patients may be at increased risk for anaphylaxis and infusion reactions, when treatment is discontinued for >4 weeks, due to potential to immunogenicity

Administered by IV infusion over no less than 120 min via gravity feed, syringe-type pump, or infusion pump

Pre-medicate patients with antihistamines and corticosteroids before treating

Monitor serum uric acid levels before each infusion

Pregnancy Category: C

Lactation: Unknown whether distributed in breast milk; if it is distributed into breast milk, the potential for serious adverse reactions exist, therefore breastfeeding is not recommended

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

No Krystexxa drug interactions have been studied by the manufacturer. However, you should tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Not all drug interactions are known or reported and new drug interactions are continually being reported.

Serious side effects have been reported with Krystexxa including the following:

• serious allergic reactions. Serious allergic reactions may occur in some people taking Krystexxa. These allergic reactions can be life threatening and usually happen within 2 hours of the infusion. Your doctor or nurse will watch for any signs of a serious allergic reaction during and after your treatment with Krystexxa. Tell your doctor or nurse right away if you experience wheezing, shortness of breath, cough, chest tightness, chest pain, or trouble breathing. It is also important to let your doctor know if you experience reddening of the face, itching, hives, swelling of the throat or tongue, throat tightness, hoarse voice, or trouble swallowing.

Krystexxa can cause dizziness. Do not drive or operate heavy machinery until you know how Krystexxa affects you.

Do not take Krystexxa if you:

• are allergic to Krystexxa or to any of its ingredients
• have glucose-6-phosphate dehydrogenase (G6PD) deficiency (genetic disorder that can affect the red blood cells)

If Krystexxa is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

You may receive medications before receiving Krystexxa to prevent side effects from the injection.

Pegylated biosynthetic (recombinant DNA origin) modified mammalian urate oxidase (uricase) enzyme.1 7 8 11

• Pegloticase medication guide must be provided to the patient each time the drug is administered (see REMS Program under Dosage and Administration);5 importance of patient reading the medication guide before initiating therapy and before each subsequent infusion.1 2

• Importance of informing patients that anaphylaxis and infusion reactions can occur with any infusion.1 Importance of informing patients of the signs and symptoms of anaphylaxis (e.g., wheezing, swelling of the throat or tongue, throat tightness, hoarseness, difficulty swallowing, dizziness, fainting, fast or weak heartbeat, feelings of nervousness, rash, itching, urticaria)1 2 and infusion reactions (e.g., urticaria, erythema, difficulty breathing, flushing, chest discomfort or pain, rash).1

• Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after an infusion of pegloticase.1 Counsel patients on the importance of adhering to therapy prescribed to prevent or lessen the severity of these reactions.1

• Importance of informing patients not to take pegloticase if they have G-6-PD deficiency.1 Counsel patients that they may be tested to determine if they have G-6-PD deficiency.1

• Importance of informing patients that gout flares may initially increase when starting treatment with pegloticase and that medications to help reduce flares may be taken regularly for the first few months after initiation.1 Advise patients that they should not discontinue pegloticase if flares occur.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or dietary supplements, as well as any concomitant conditions (e.g., heart failure, G-6-PD deficiency).1 2

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

A nurse or other trained health professional will give you this medicine in a hospital or clinic. This medicine is given through a needle placed in one of your veins.

This medicine must be given slowly, so the needle will remain in place for a few hours (up to 2 hours or longer). You may also receive medicines (eg, antihistamines, corticosteroids) to help prevent possible allergic reactions to the injection.

This medicine is usually given every 2 weeks. If you miss a dose or forget to receive your medicine, call your doctor for instructions.

This medicine should come with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Chest pain or pressure.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.

The efficacy of Krystexxa 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 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 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 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 every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. Although the 4 week regimen also 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.

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 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 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 8 mg every 2 weeks, Krystexxa 8 mg every 4 weeks, and placebo, respectively. The difference between Krystexxa and placebo was statistically significant for the every 2 week dosing regimen, but not for the every 4 week dosing regimen.

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 (5.1, 5.2), Adverse Reactions (6.1)]
  
• Advise patients to discontinue any oral urate-lowering agents before starting on Krystexxa and not to take any oral urate-lowering agents while on Krystexxa.

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency
Inform patients not to take Krystexxa if they have a condition known as G6PD deficiency. Explain to patients that G6PD deficiency is more frequently found in individuals of African, Mediterranean, or Southern Asian ancestry and that they may be tested to determine if they have G6PD deficiency, unless already known. [See Warnings and Precautions (5.3), Contraindications (4)]

Gout Flares
Explain to patients that gout flares may initially increase when starting treatment with Krystexxa, and that medications to help reduce flares may need to be taken regularly for the first few months after Krystexxa is started. [see Warnings and Precautions (5.4), Adverse Reactions (6.1)] Advise patients that they should not stop Krystexxa therapy if they have a flare.

Manufactured by:
Horizon Pharma Rheumatology LLC
Lake Forest, IL 60045
US License Number 2048

Distributed by:
Horizon Pharma USA, Inc.
Lake Forest, IL 60045

Medication Guide
Krystexxa®
(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 6-phosphate 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 Horizon Pharma Rheumatology LLC at 1-866-479-6742.

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.horizonpharma.com or call 1-866-479-6742.

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.

Product manufactured by:
Horizon Pharma Rheumatology LLC
Lake Forest, IL 60045
US License Number 2048

Product Distributed by:
Horizon Pharma USA, Inc.
Lake Forest, IL 60045

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 09/2016 

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

Some drugs can interact with Krystexxa 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 Krystexxa 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 Krystexxa 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 this medicine.

Krystexxa is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. The injection 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 Krystexxa. You may need to start taking these medications at least a week before you receive your Krystexxa 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.

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

When you first start using Krystexxa, 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 Krystexxa.

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 Krystexxa. Visit your doctor regularly.

Some people receiving a Krystexxa 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 to Krystexxa: 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 Krystexxa 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.

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