Arcalyst

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

Serious and sometimes fatal infections may occur during treatment with rilonacept. Call your doctor right away if you have any new signs of infection such as:

• fever, chills, sore throat, flu symptoms;
• easy bruising or bleeding (nosebleeds, bleeding gums);
• nausea and vomiting, loss of appetite;
• mouth sores; or
• unusual weakness.

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

• bloody, black, or tarry stools;
• coughing up blood or vomit that looks like coffee grounds;
• wheezing, chest tightness, trouble breathing;
• pain or burning when you urinate; or
• headache, neck stiffness, increased sensitivity to light, purple spots on the skin, and/or seizure (convulsions).

Other common side effects may include:

• cold symptoms such as stuffy nose, sneezing, cough, sore throat;
• nausea, stomach pain, diarrhea;
• numbness or tingly feeling; or
• pain, swelling, redness, itching, warmth, blistering, bleeding, or other irritation where the medicine was injected.

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.

Mechanism Of Action

CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [Nucleotidebinding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold- Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.

In most cases, inflammation in CAPS is associated with mutations in the NLRP-3 gene which encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation.

Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist (IL- 1ra) with reduced affinity. The equilibrium dissociation constants for rilonacept binding to IL-1β, IL-1α and IL-1ra were 0.5 pM, 1.4 pM and 6.1 pM, respectively.

Pharmacodynamics

C-Reactive Protein (CRP) and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Compared to placebo, treatment with ARCALYST resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. ARCALYST also normalized mean SAA from elevated levels.

Pharmacokinetics

The average trough levels of rilonacept were approximately 24 mcg/mL at steady-state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady-state appeared to be reached by 6 weeks.

No pharmacokinetic data are available in patients with hepatic or renal impairment.

No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical study, reflecting the epidemiology of the disease.

Clinical Studies

The safety and efficacy of ARCALYST for the treatment of CAPS was demonstrated in a randomized, double-blind, placebo-controlled study with two parts (A and B) conducted sequentially in the same patients with FCAS and MWS.

Part A was a 6-week, randomized, double-blind, parallel-group period comparing ARCALYST at a dose of 160 mg weekly after an initial loading dose of 320 mg to placebo. Part B followed immediately after Part A and consisted of a 9-week, patient-blind period during which all patients received ARCALYST 160 mg weekly, followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on ARCALYST 160 mg weekly or to receive placebo. Patients were then given the option to enroll in a 24-week, open-label treatment extension phase in which all patients were treated with ARCALYST 160 mg weekly.

Using a daily diary questionnaire, patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). The study evaluated the mean symptom score using the change from baseline to the end of treatment.

The changes in mean symptom scores for the randomized parallel-group period (Part A) and the randomized withdrawal period (Part B) of the study are shown in Table 2. ARCALYST-treated patients had a larger reduction in the mean symptom score in Part A compared to placebo-treated patients. In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on ARCALYST.

Table 2: Mean Symptom Scores

Daily mean symptom scores over time for Part A are shown in Figure 1.

Figure 1: Group Mean Daily Symptom Scores by Treatment Group in Part A and Single-blind ARCALYST Treatment Phase from Week -3 to Week 15

Improvement in symptom scores was noted within several days of initiation of ARCALYST therapy in most patients.

In Part A, patients treated with ARCALYST experienced more improvement in each of the five components of the composite endpoint (joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue) than placebo-treated patients.

In Part A, a higher proportion of patients in the ARCALYST group experienced improvement from baseline in the composite score by at least 30% (96% vs. 29% of patients), by at least 50% (87% vs.8%) and by at least 75% (70% vs. 0%) compared to the placebo group.

Serum Amyloid A (SAA) and C-Reactive Protein (CRP) levels are acute phase reactants that are typically elevated in patients with CAPS with active disease. During Part A, mean levels of CRP decreased versus baseline for the ARCALYST treated patients, while there was no change for those on placebo (Table 3). ARCALYST also led to a decrease in SAA versus baseline to levels within the normal range.

Table 3: Mean Serum Amyloid A and C-Reactive Protein Levels Over Time in Part A

During the open-label extension, reductions in mean symptom scores, serum CRP, and serum SAA levels were maintained for up to one year.

Arcalyst is a prescription medication used to treat rare genetic auto-inflammatory conditions called Cryopyrin-Associated Periodic Syndromes (CAPS). This includes conditions known as Familial Cold Auto-Inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 and older.

Arcalyst belongs to a group of drugs called interleukin-1 blockers. These work by blocking the activity of a certain protein responsible for inflammation.

This medication is available in an injectable form to be given directly under the skin (subcutaneously) once weekly.

Common side effects of Arcalyst include upper respiratory infections and injection site reactions.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends will depend on your age.

The recommended loading dose for patients 18 years or older is 320 mg (given as 2 different injections on the same day), followed by one injection of 160 mg once weekly.

The recommended initial loading dose for patients age 12 to 17 years is one dose of 4.4 mg per kg body weight, up to a maximum of 320 mg (given as 1 or 2 injections depending on the dose). Dosing should be continued with one injection of 2.2 mg/kg, up to a maximum of 160 mg, once weekly.

Serious and sometimes fatal infections may occur during treatment with rilonacept. Call your doctor right away if you have signs of infection such as: fever, chills, sore throat, flu symptoms, easy bruising or bleeding (nosebleeds, bleeding gums), loss of appetite, nausea and vomiting, mouth sores, or unusual weakness.

You should not use this medication if you are allergic to rilonacept, or if you have any type of infection.

Before using rilonacept, tell your doctor if you have an active or chronic infection, a history of tuberculosis or recurrent infections, or high cholesterol or triglycerides. Make sure you are current on all vaccines before you start treatment with rilonacept.

Tell your doctor about all other medications you use, especially drugs to treat arthritis, psoriasis, Crohn's disease, or ankylosing spondylitis.

Do not receive a "live" vaccine while using rilonacept. The vaccine may not work as well during this time, and may not fully protect you from disease. Avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

You should not use this medication if you are allergic to rilonacept, or if you have any type of infection.

To make sure rilonacept is safe for you, tell your doctor if you have any of these conditions:

• an active or chronic infection;

• a history of tuberculosis or recurrent infections; or

• high cholesterol or triglycerides (a type of fat in blood).

Make sure you are current on all vaccines before you start treatment with rilonacept.

Using rilonacept may increase your risk of developing certain types of cancer. Talk with your doctor about your specific risk.

FDA pregnancy category C. It is not known whether rilonacept 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 rilonacept passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give this medicine to a child younger than 12 years old without medical advice.

Do not receive a "live" vaccine while using rilonacept. The vaccine may not work as well during this time, and may not fully protect you from disease. Avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Live vaccines include: measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, smallpox, yellow fever, varicella (chickenpox), zoster (shingles), oral typhoid vaccine, and nasal flu (influenza) vaccine.

• Importance of providing a copy of the manufacturer’s patient information to all patients.1 3 Importance of discussing any questions pertaining to the manufacturer’s patient information.1 3

• Importance of instructing patient and/or caregiver regarding proper dosage and administration of rilonacept (including the use of aseptic technique and safe disposal of vials, needles, and syringes) if clinician has determined that the drug can safely and effectively be self-administered in the patient’s home by the patient, family member, or other responsible individual.1 3

• Risk of injection site reactions (e.g., erythema, swelling, pruritus, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth, hemorrhage).1 Importance of not injecting into areas where the skin is bruised, red, swollen, tender, or hard.1 Importance of informing clinician of any persistent injection site reaction.1

• Risk of serious, potentially life-threatening infection.1 Importance of informing clinicians promptly if any signs or symptoms of infection (e.g., fever, cough, flu-like symptoms, open sores) occur.1 3

• Risk of hypersensitivity reactions.1 Importance of immediately contacting a clinician or seeking immediate medical attention if any signs or symptoms of hypersensitivity (e.g., rash, swollen face, difficulty breathing) occur.1

• Possible changes in blood cholesterol and triglyceride concentrations; importance of adherence to laboratory appointment schedules.1

• Importance of reviewing vaccination status with clinician and receiving all age-appropriate vaccines prior to initiation of rilonacept therapy.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., IL-1 antagonists, TNF-blocking agents, immunizations, corticosteroids) or OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses (e.g., active or chronic infections, asthma, diabetes mellitus).1 3

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 3

• Importance of informing patients of other important precautionary information.1 3 (See Cautions.)

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.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Numbness or tingling.
• Very bad irritation where the shot was given.
• Throwing up blood or throw up that looks like coffee grounds.
• Black, tarry, or bloody stools.
• Belly pain.

General Dosing Information

Injection for Subcutaneous Use Only.

Dosing

Adult patients 18 years and older: Treatment should be initiated with a loading dose of 320 mg delivered as two, 2-mL, subcutaneous injections of 160 mg each given on the same day at two different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection. Arcalyst should not be given more often than once weekly. Dosage modification is not required based on advanced age or gender.

Pediatric patients aged 12 to 17 years: Treatment should be initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. If the initial dose is given as two injections, they should be given on the same day at two different sites. Arcalyst should not be given more often than once weekly.

Preparation for Administration

Each single-use vial of Arcalyst contains a sterile, white to off-white, preservative-free, lyophilized powder. Reconstitution with 2.3 mL of preservative-free Sterile Water for Injection (supplied separately) is required prior to subcutaneous administration of the drug.

Administration

Using aseptic technique, withdraw 2.3 mL of preservative-free Sterile Water for Injection through a 27-gauge, ½-inch needle attached to a 3-mL syringe and inject the preservative-free Sterile Water for Injection into the drug product vial for reconstitution. The needle and syringe used for reconstitution with preservative-free Sterile Water for Injection should then be discarded and should not be used for subcutaneous injections. After the addition of preservative-free Sterile Water for Injection, the vial contents should be reconstituted by shaking the vial for approximately one minute and then allowing it to sit for one minute. The resulting 80-mg/mL solution is sufficient to allow a withdrawal volume of up to 2 mL for subcutaneous administration. The reconstituted solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Prior to injection, the reconstituted solution should be carefully inspected for any discoloration or particulate matter. If there is discoloration or particulate matter in the solution, the product in that vial should not be used.

Using aseptic technique, withdraw the recommended dose volume, up to 2 mL (160 mg), of the solution with a new 27-gauge, ½-inch needle attached to a new 3-mL syringe for subcutaneous injection. EACH VIAL SHOULD BE USED FOR A SINGLE DOSE ONLY. Discard the vial after withdrawal of drug.

Sites for subcutaneous injection, such as the abdomen, thigh, or upper arm, should be rotated. Injections should never be made at sites that are bruised, red, tender, or hard.

Stability and Storage

The lyophilized Arcalyst product is to be stored refrigerated at 2° to 8°C (36° to 46°F) inside the original carton to protect it from light. Do not use beyond the date stamped on the label. After reconstitution, Arcalyst may be kept at room temperature, should be protected from light, and should be used within three hours of reconstitution. Arcalyst does not contain preservatives; therefore, unused portions of Arcalyst should be discarded.

TNF-Blocking Agent and IL-1 Blocking Agent

Specific drug interaction studies have not been conducted with Arcalyst. Concomitant administration of another drug that blocks IL-1 with a TNF-blocking agent in another patient population has been associated with an increased risk of serious infections and an increased risk of neutropenia. The concomitant administration of Arcalyst with TNF-blocking agents may also result in similar toxicities and is not recommended [see Warnings and Precautions (5.1)]. The concomitant administration of Arcalyst with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacologic interactions between rilonacept and a recombinant IL-1ra, concomitant administration of Arcalyst and other agents that block IL-1 or its receptors is not recommended.

Cytochrome P450 Substrates

The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of Arcalyst, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed.

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies of Arcalyst in pregnant women. Based on animal data, Arcalyst may cause fetal harm. An embryo-fetal developmental toxicity study was performed in cynomolgus monkeys treated with 0, 5, 15 or 30 mg/kg given twice a week (highest dose is approximately 3.7-fold higher than the human doses of 160 mg based on body surface area). The fetus of the only monkey with exposure to rilonacept during the later period of gestation showed multiple fusion and absence of the ribs and thoracic vertebral bodies and arches. Exposure to rilonacept during this time period was below that expected clinically. Likewise, in the cynomolgus monkey, all doses of rilonacept reduced serum levels of estradiol up to 64% compared to controls and increased the incidence of lumbar ribs compared to both control animals and historical control incidences. In perinatal and postnatal developmental toxicology studies in the mouse model using a murine analog of rilonacept (0, 20, 100 or 200 mg/kg), there was a 3-fold increase in the number of stillbirths in dams treated with 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Arcalyst should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Nonteratogenic effects. A peri- and post-natal reproductive toxicology study was performed in which mice were subcutaneously administered a murine analog of rilonacept at doses of 20, 100, 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Results indicated an increased incidence in unscheduled deaths of the F1 offspring during maturation at all doses tested.

Nursing Mothers

It is not known whether rilonacept is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Arcalyst is administered to a nursing woman.

Pediatric Use

Six pediatric patients with CAPS between the ages of 12 and 16 were treated with Arcalyst at a weekly, subcutaneous dose of 2.2 mg/kg (up to a maximum of 160 mg) for 24-weeks during the open-label extension phase. These patients showed improvement from baseline in their symptom scores and in objective markers of inflammation (e.g. Serum Amyloid A and C-Reactive Protein). The adverse events included injection site reactions and upper respiratory symptoms as were commonly seen in the adult patients.

The trough drug levels for four pediatric patients measured at the end of the weekly dose interval (mean 20 mcg/mL, range 3.6 to 33 mcg/mL) were similar to those observed in adult patients with CAPS (mean 24 mcg/mL, range 7 to 56 mcg/mL).

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if Arcalyst will alter bone development in pediatric patients. Pediatric patients treated with Arcalyst should undergo appropriate monitoring for growth and development. [see Use in Specific Populations (8.1)]

Geriatric Use

In the placebo-controlled clinical studies in patients with CAPS and other indications, 70 patients randomized to treatment with Arcalyst were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71 year old woman developed bacterial meningitis and died [see Adverse Reactions (6.3)]. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study.

Patients with Renal Impairment

No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment.

Patients with Hepatic Impairment

No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment.

Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept has a molecular weight of approximately 251 kDa. Rilonacept is expressed in recombinant Chinese hamster ovary (CHO) cells.

Arcalyst is supplied in single-use, 20-mL glass vials containing a sterile, white to off-white, lyophilized powder. Each vial of Arcalyst is to be reconstituted with 2.3 mL of Sterile Water for Injection. A volume of up to 2 mL can be withdrawn, which is designed to deliver 160 mg for subcutaneous administration only. The resulting solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Each vial contains 220 mg rilonacept. After reconstitution, each vial contains 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5 ± 0.3. No preservatives are present.

NDC 61755-001-01

Arcalyst®

(rilonacept)

Injection for Subcutaneous Use

220 mg sterile powder for reconstitution

Store at 2-8°C (36-46°F) until use.

Protect from light.

Contents: four (4) single-use vials

Rx ONLY

REGENERON

• Inflectra

© Arcalyst Patient Information is supplied by Cerner Multum, Inc. and Arcalyst Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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

Do not receive a "live" vaccine while using Arcalyst. The vaccine may not work as well during this time, and may not fully protect you from disease. Avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Live vaccines include: measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, smallpox, yellow fever, varicella (chickenpox), zoster (shingles), oral typhoid vaccine, and nasal flu (influenza) vaccine.