Vial and Pre-Filled Syringe: Atlizumab, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with ≥1 disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists.

In these patients, Atlizumab can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Atlizumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.

Vial: Atlizumab, in combination with methotrexate (MTX), is indicated for the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

Atlizumab is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients ≥2 years, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. Atlizumab can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.

Atlizumab in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. Atlizumab can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Atlizumab reduces the effects of a substance in the body that can cause inflammation.

Atlizumab is used to treat moderate to severe rheumatoid arthritis in adults. It is sometimes given together with other arthritis medicines.

Atlizumab is also used to treat systemic juvenile idiopathic arthritis (or "Still disease") in children who are at least 2 years old. It is sometimes given together with methotrexate (Rheumatrex, Trexall).

Atlizumab is usually given after other medications have been tried without successful treatment of symptoms.

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

Rheumatoid Arthritis

Atlizumab may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.

Recommended

Intravenous (IV) Dosage Regimen

The recommended dosage of Atlizumab for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Doses exceeding 800 mg per infusion are not recommended in RA patients.

Recommended Subcutaneous (SC) Dosage Regimen

When transitioning from Atlizumab intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

Polyarticular Juvenile Idiopathic Arthritis

Atlizumab may be used alone or in combination with methotrexate. The recommended dosage of Atlizumab for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Recommended

Intravenous PJIA Dosage Every 4 Weeks

• Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Subcutaneous administration is not approved for PJIA.

Systemic Juvenile Idiopathic Arthritis

Atlizumab may be used alone or in combination with methotrexate. The recommended dose of Atlizumab for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:

Recommended

Intravenous SJIA Dosage Every 2 Weeks

• Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Subcutaneous administration is not approved for SJIA.

General Considerations For Administration

• Atlizumab has not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using Atlizumab with biological DMARDs.
• It is recommended that Atlizumab not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).

Preparation And Administration Instructions For

Intravenous Infusion

Atlizumab for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

• PJIA and SJIA patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% Sodium Chloride, and then follow steps 1 and 2 below.
• Adult RA, PJIA and SJIA patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below.
  • Step 1. Withdraw a volume of 0.9% Sodium Chloride injection, equal to the volume of the Atlizumab injection required for the patient's dose from the infusion bag or bottle.

For

Intravenous Use: Volume of Atlizumab Injection per kg of Body Weight

• Step 2. Withdraw the amount of Atlizumab for intravenous infusion from the vial(s) and add slowly into the Sodium Chloride infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
• The fully diluted Atlizumab solutions for infusion may be stored at 2° to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light. Atlizumab solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
• Allow the fully diluted Atlizumab solution to reach room temperature prior to infusion.
• The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
• Atlizumab should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Atlizumab with other drugs.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.

• Fully diluted Atlizumab solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

Preparation And Administration Instructions For Subcutaneous Injection For RA

• Atlizumab for subcutaneous injection is only indicated in the treatment in patients with adult RA and is not indicated for the treatment of patients with PJIA or SJIA. Atlizumab for subcutaneous injection is not intended for intravenous drip infusion.
• Atlizumab injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject Atlizumab or the patient's caregiver may administer Atlizumab if a healthcare practitioner determines that it is appropriate. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use Atlizumab prefilled syringes (PFS) exhibiting particulate matter, cloudiness, or discoloration. Atlizumab for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS appears to be damaged.

• Patients using Atlizumab for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL), which provides 162 mg of Atlizumab, according to the directions provided in the IFU.
• Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Dosage Modifications Due To Serious Infections Or Laboratory Abnormalities

Hold Atlizumab treatment if a patient develops a serious infection until the infection is controlled.

Rheumatoid Arthritis

Liver Enzyme Abnormalities :

Polyarticular And Systemic Juvenile Idiopathic Arthritis:

Dose reduction of Atlizumab has not been studied in the PJIA and SJIA populations. Dose interruptions of Atlizumab are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold Atlizumab dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue Atlizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.

How supplied

Dosage Forms And Strengths

Single-use Vials of Atlizumab (20 mg per mL) for IV Administration

• 80 mg per 4 mL
• 200 mg per 10 mL
• 400 mg per 20 mL

Prefilled Syringe (PFS) for SC Administration

• A single-use prefilled glass syringe providing 162 mg of Atlizumab in 0.9mL

Storage And Handling

For

Intravenous Infusion

Atlizumab (Atlizumab) is supplied in single-use vials as a preservative-free, sterile concentrate (20 mg per mL) solution for intravenous infusion. The following packaging configurations are available:

Individually packaged, single-use vials:

NDC 50242-135-01 providing 80 mg per 4 mL

NDC 50242-136-01 providing 200 mg per 10 mL

NDC 50242-137-01 providing 400 mg per 20 mL

For Subcutaneous Injection

Atlizumab (Atlizumab) for subcutaneous administration is supplied as a sterile preservative-free liquid solution in a single-use prefilled syringe. The following packaging configurations are available:

NDC 50242-138-01 prefilled syringe providing 162 mg per 0.9mL

Storage and Stability: Do not use beyond expiration date on the container, package or prefilled syringe. Atlizumab must be refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect the vials and syringes from light by storage in the original package until time of use, and keep syringes dry.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particles are observed, the solution should not be used.

Genentech, Inc., A Member of the Roche Group 1 DNA Way, South San Francisco, CA 94080-4990. Revised: Sep 2016

See also:
What is the most important information I should know about Atlizumab?

Serious and sometimes fatal infections may occur during treatment with Atlizumab. Contact your doctor right away if you have signs of infection such as: fever, chills, body aches, flu symptoms, cough, sweating, feeling short of breath, diarrhea, weight loss, sores on your skin, painful urination, or feeling very tired.

Before you start treatment with Atlizumab, your doctor may perform tests to make sure you do not have tuberculosis or other infections.

Tell your doctor if you have an active or recent infection, liver disease or hepatitis B, diabetes, diverticulitis, stomach ulcer or bleeding, high cholesterol, multiple sclerosis, HIV/AIDS, a weak immune system, or a history of cancer.

Atlizumab can lower the blood cells that help your body fight infections. Avoid being near people who are sick or have infections.

Do not receive a "live" vaccine while you are being treated with Atlizumab.

Treatment with Atlizumab may increase your risk of developing certain types of cancer. Talk to your doctor about your specific risk.

Use Atlizumab as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Atlizumab comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Atlizumab refilled.
• Atlizumab is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Atlizumab at home, a health care provider will teach you how to use it. Be sure you understand how to use Atlizumab. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.
• Do not use Atlizumab if it contains particles, is cloudy or discolored, or if the syringe is cracked or damaged.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Atlizumab, contact your doctor.

Ask your health care provider any questions you may have about how to use Atlizumab.

This medication is used alone or with other medications to treat moderate to severe rheumatoid arthritis in adults. It helps to reduce pain and swelling due to rheumatoid arthritis. Atlizumab belongs to a class of drugs known as Interleukin-6 (IL-6) blockers. It works by blocking IL-6, a substance made by the body that causes swelling (inflammation).

How to use Atlizumab

Read the Medication Guide and Instructions for Use provided by your pharmacist before you start using Atlizumab and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

If you are using this medication at home, learn all preparation and usage instructions from your health care professional and the product package.

Remove one syringe from the refrigerator 30 minutes before using it to allow it to reach room temperature. Do not speed up the warming process in any way; for example, do not use the microwave or place the syringe in warm water. Check this product visually for particles or discoloration. If either is present, do not use the liquid.

Inject this medication under the skin as directed by your doctor, usually starting with once every 2 weeks, then increasing to once a week. Recommended injection sites include the abdomen or the front of your thigh. The outer area of the upper arms may also be used if another person is giving you the injection. Before injecting each dose, clean the injection site with rubbing alcohol. Change the injection site each time to lessen injury under the skin. Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard, or broken.

Learn how to store and discard medical supplies safely.

The dosage is based on your weight, laboratory tests, and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, mark the days you need to inject the medication on a calendar.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Atlizumab?

Other Drugs For Treatment Of Rheumatoid Arthritis

Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on Atlizumab clearance.

Concomitant administration of a single intravenous dose of 10 mg per kg Atlizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.

Atlizumab has not been studied in combination with biological DMARDs such as TNF antagonists.

Interactions With CYP450 Substrates

Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with Atlizumab may restore CYP450 activities to higher levels than those in the absence of Atlizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that Atlizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of Atlizumab, respectively. The effect of Atlizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Atlizumab, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering Atlizumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of Atlizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Live Vaccines

Avoid use of live vaccines concurrently with Atlizumab.

Drug Abuse And Dependence

No studies on the potential for Atlizumab to cause dependence have been performed. However, there is no evidence from the available data that Atlizumab treatment results in dependence.

See also:
What are the possible side effects of Atlizumab?

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the 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.

Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With

Intravenous Atlizumab (Atlizumab-IV)

The Atlizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Atlizumab-IV 8 mg per kg monotherapy (288 patients), Atlizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Atlizumab-IV 4 mg per kg in combination with methotrexate (774 patients).

The all exposure population includes all patients in registration studies who received at least one dose of Atlizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.

All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with Atlizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking Atlizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Atlizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.

Overall Infections

In the 24 week, controlled clinical studies, the rate of infections in the Atlizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg Atlizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.

The overall rate of infections with Atlizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.

Serious Infections

In the 24 week, controlled clinical studies, the rate of serious infections in the Atlizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg Atlizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.

Gastrointestinal Perforations

During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with Atlizumab-IV therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate. The relative contribution of these concomitant medications versus Atlizumab-IV to the development of GI perforations is not known.

Infusion Reactions

In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg Atlizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.

Anaphylaxis

Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with Atlizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of Atlizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction.

Laboratory Abnormalities

Neutropenia

In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm³ occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Atlizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm³ occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm³ occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg Atlizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm³ and the occurrence of serious infections.

In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies.

Thrombocytopenia

In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm³ occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg Atlizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.

In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies.

Elevated Liver Enzymes

Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Atlizumab-IV, or reduction in Atlizumab-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.

Table 1 : Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V*

In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials

Lipids

Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of Atlizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:

• Mean LDL increased by 13 mg per dL in the Atlizumab 4 mg per kg+DMARD arm, 20 mg per dL in the Atlizumab 8 mg per kg+DMARD, and 25 mg per dL in Atlizumab 8 mg per kg monotherapy.
• Mean HDL increased by 3 mg per dL in the Atlizumab 4 mg per kg+DMARD arm, 5 mg per dL in the Atlizumab 8 mg per kg+DMARD, and 4 mg per dL in Atlizumab 8 mg per kg monotherapy.
• Mean LDL/HDL ratio increased by an average of 0.14 in the Atlizumab 4 mg per kg+DMARD arm, 0.15 in the Atlizumab 8 mg per kg+DMARD, and 0.26 in Atlizumab 8 mg per kg monotherapy.
• ApoB/ApoA1 ratios were essentially unchanged in Atlizumab-treated patients.

Elevated lipids responded to lipid lowering agents.

In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.

Immunogenicity

In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-Atlizumab antibodies. Forty-six patients (2%) developed positive anti-Atlizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.

The data reflect the percentage of patients whose test results were positive for antibodies to Atlizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to Atlizumab with the incidence of antibodies to other products may be misleading.

Malignancies

During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving Atlizumab-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Atlizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).

In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period.

Other Adverse Reactions

Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg Atlizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.

Table 2 : Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Atlizumab plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD

Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with Atlizumab-IV in controlled trials were:

Infections and Infestations: oral herpes simplex

Gastrointestinal disorders: stomatitis, gastric ulcer

Investigations: weight increased, total bilirubin increased

Blood and lymphatic system disorders: leukopenia

General disorders and administration site conditions: edema peripheral

Respiratory, thoracic, and mediastinal disorders: dyspnea, cough

Eye disorders: conjunctivitis

Renal disorders: nephrolithiasis

Endocrine disorders: hypothyroidism

Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With Subcutaneous Atlizumab (Atlizumab-SC)

The Atlizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of Atlizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of Atlizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.

The safety observed for Atlizumab administered subcutaneously was consistent with the known safety profile of intravenous Atlizumab, with the exception of injection site reactions, which were more common with Atlizumab-SC compared with placebo SC injections (IV arm).

Injection Site Reactions

In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly Atlizumab-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC Atlizumab and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.

Immunogenicity

In the 6-month control period in SC-I, 0.8% (5/625) in the Atlizumab-SC arm and 0.8% (5/627) in the IV arm developed anti-Atlizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the Atlizumab-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- Atlizumab antibodies; of these, 1.4% (6/434) in the Atlizumab-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.

A total of 1454 ( > 99%) patients who received Atlizumab-SC in the all exposure group have been tested for anti-Atlizumab antibodies. Thirteen patients (0.9%) developed anti-Atlizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.

The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.

Laboratory Abnormalities

Neutropenia

During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 x 10/L and the occurrence of serious infections.

Thrombocytopenia

During routine laboratory monitoring in the Atlizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤ 50 x 103/mcL.

Elevated Liver Enzymes

During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥ 3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving Atlizumab-SC weekly and 3.4% and 0.7% receiving Atlizumab SC every other week.

Lipids

During routine laboratory monitoring in the Atlizumab-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving Atlizumab-SC weekly, every other week and placebo, respectively.

Clinical Trials Experience In Polyarticular Juvenile Idiopathic Arthritis Patients Treated With

Intravenous Atlizumab (Atlizumab-IV)

The safety of Atlizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the ACTEMRAIV all exposure population (defined as patients who received at least one dose of Atlizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients.

Infections

The rate of infections in the Atlizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg Atlizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg Atlizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg Atlizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg Atlizumab (8%).

Infusion Reactions

In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Atlizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients.

No clinically significant hypersensitivity reactions associated with Atlizumab and requiring treatment discontinuation were reported.

Immunogenicity

One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-Atlizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

Laboratory Abnormalities

Neutropenia

During routine laboratory monitoring in the Atlizumab-IV all exposure population, a decrease in neutrophil counts below 1 x 109 per L occurred in 3.7% of patients.

There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections.

Thrombocytopenia

During routine laboratory monitoring in the Atlizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50 x 103 per mcL without associated bleeding events.

Elevated Liver Enzymes

During routine laboratory monitoring in the Atlizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively.

Lipids

During routine laboratory monitoring in the Atlizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%).

Clinical Trials Experience In Systemic Juvenile Idiopathic Arthritis Patients Treated With

Intravenous Atlizumab (Atlizumab-IV)

The data described below reflect exposure to Atlizumab-IV in one randomized, double-blind, placebocontrolled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with Atlizumab-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Atlizumab-IV in the open-label extension phase.

The most common adverse events (at least 5%) seen in Atlizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.

Infections

In the 12 week controlled phase, the rate of all infections in the Atlizumab-IV group was 345 per 100 patientyears and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.

In the 12 week controlled phase, the rate of serious infections in the Atlizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.

Macrophage Activation Syndrome

In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with Atlizumab-IV. One patient in the placebo group escaped to Atlizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had Atlizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the Atlizumab-IV SJIA clinical development experience; however no definitive conclusions can be made.

Infusion Reactions

Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of Atlizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and lifethreatening, and the patient was discontinued from study treatment.

Within 24 hours after infusion, 16% of patients in the Atlizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the Atlizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.

Anaphylaxis

Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with Atlizumab-IV during the controlled and open label extension study.

Immunogenicity

All 112 patients were tested for anti-Atlizumab antibodies at baseline. Two patients developed positive antitocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.

Laboratory Abnormalities

Neutropenia

During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 x 109 per L occurred in 7% of patients in the Atlizumab-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the Atlizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections.

Thrombocytopenia

During routine monitoring in the 12 week controlled phase, 1% of patients in the Atlizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100 x 103 per mcL.

In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the Atlizumab-IV group, with no associated bleeding.

Elevated Liver Enzymes

During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the Atlizumab-IV group and in 0% of placebo patients.

In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of Atlizumab-IV treated patients, respectively.

Lipids

During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN - 2x ULN occurred in 1.5% of the Atlizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN - 2x ULN occurred in 1.9% of patients in the Atlizumab-IV group and 0% of the placebo group.

In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of intravenous Atlizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Fatal anaphylaxis
• Stevens-Johnson Syndrome

Vial: Atlizumab is supplied in 10 mL and 20 mL vials containing 4 mL, 10 mL or 20 mL of Atlizumab (20 mg/mL).

Pre-Filled Syringe: Each pre-filled syringe contains 162 mg of Atlizumab in 0.9 mL.

Atlizumab is a recombinant humanized, anti-human monoclonal antibody of theimmunoglobulin G1 (IgG₁) sub-class directed against soluble and membrane-bound interleukin-6 (IL-6) receptors.

Excipients/Inactive Ingredients: Vial: Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate and water for injections.

Pre-filled Syringe: L-histidine, L-histidine monohydrochloride monohydrate, L-arginine, L-arginine hydrochloride, L-methionine, polysorbate 80, water for injections.