These Highlights Do Not Include All The Information Needed To Use Enspryng Safely And Effectively. See Full Prescribing Information For Enspryng.

Hepatitis B Virus Screening

Prior to initiating ENSPRYNG, perform Hepatitis B virus (HBV) screening. ENSPRYNG is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1)].

Satralizumab-mwge is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody based on a human IgG2 framework. Each light chain and heavy chain consists of 214 and 443 amino acids, respectively. Satralizumab-mwge is a glycoprotein with an approximate molecular weight of 143 kDa and is produced by recombinant DNA technology in Chinese hamster ovary cells. The binding of satralizumab-mwge to the IL-6 receptor is pH-sensitive.

ENSPRYNG (satralizumab-mwge) injection for subcutaneous administration is supplied as a sterile, clear, colorless to slightly yellow solution with no preservative with an approximate pH of 6. ENSPRYNG is supplied in a single-dose prefilled syringe. Each syringe delivers 1 mL of solution containing 120 mg of satralizumab-mwge, L-arginine (26.1 mg), L-histidine (3.1 mg), poloxamer 188 (0.5 mg), L-aspartic acid (pH adjustment), and Water for Injection, USP.

An increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG.

The most common infections reported in a randomized clinical trial of patients treated with ENSPRYNG who were not on other chronic immunosuppressant therapies (Study 1), and that occurred more often than in patients receiving placebo, were nasopharyngitis (12%) and cellulitis (10%). The most common infections in patients who were on an additional concurrent immunosuppressant, and that occurred more often than in patients receiving placebo, were nasopharyngitis (31%), upper respiratory infection (19%), and pharyngitis (12%).

Delay ENSPRYNG administration in patients with an active infection, including localized infections, until the infection is resolved.

ENSPRYNG (satralizumab-mwge) injection is available as a sterile, preservative-free, clear, colorless to slightly yellow solution in single-dose prefilled syringe (PFS) with needle safety device.

ENSPRYNG PFS is not made with natural rubber latex. Each ENSPRYNG carton contains one single-dose 120 mg/mL prefilled syringe (NDC 50242-007-01).

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of satralizumab-mwge [see Clinical Pharmacology (12.3)]. In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-satralizumab-mwge antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In Study 1 and Study 2, anti-drug-antibodies (ADAs) were observed in 73% and 38% of patients receiving ENSPRYNG in the double-blind period, respectively. The ability of these ADAs to neutralize satralizumab-mwge binding is unknown. Patients with higher body weight and lower exposure were more likely to develop ADAs (irrespective of treatment with IST). Exposure was lower in ADA positive patients. Although anti-satralizumab-mwge antibody development was not found to affect the efficacy of ENSPRYNG in these patients, the available data are too limited to make definitive conclusions. Immunogenicity does not have a clinically-relevant impact on safety. Based on the available information, neither dose interruption nor modification is warranted in those patients who develop ADAs.

The efficacy of ENSPRYNG for the treatment of NMOSD in adult patients was established in two studies. Study 1 was a randomized (2:1), placebo-controlled trial in 95 patients without concurrent IST (Study 1, NCT02073279) in which 64 patients were anti-AQP4 antibody positive and 31 patients were anti-AQP4 antibody negative.

Study 2 was a randomized (1:1), placebo-controlled trial in 76 adult patients with concurrent IST (Study 2, NCT02028884). Of these, 52 adult patients were anti-AQP4 antibody positive and 24 adult patients were anti-AQP4 antibody negative.

Patients met the following eligibility criteria:

• Study 1: Clinical evidence of 1 relapse in the previous 12 months
• Study 2: Clinical evidence of at least 2 relapses in the previous 2 years, at least one of which must have occurred in the previous year
• EDSS score of 0 to 6.5 (both studies)
• Study 1: Patients were excluded if previously treated with IST within an interval specified for each such therapy
• Study 2: One of the following baseline treatments at a stable dose as a monotherapy for 8 weeks prior to baseline: azathioprine, mycophenolate mofetil, oral corticosteroids

In Study 1, 41 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 23 received placebo. Females accounted for 76% of the ENSPRYNG group and 96% of the placebo group. The remaining baseline demographic characteristics were balanced between the treatment groups. The mean age was 44 years. Fifty percent were White, 22% were Black or African-American, and 20% were Asian. The mean EDSS score was 3.8.

In Study 2, 26 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 26 received placebo. All patients were receiving either concurrent azathioprine (42%), oral corticosteroids (52%), or mycophenolate mofetil (6%) during the trial. The baseline demographic and disease characteristics were balanced between the treatment groups. Females accounted for 100% of the study population. Forty-six percent of patients were White and 52% were Asian. The mean age was 46 years. The mean EDSS score was 4.0.

All potential relapses were adjudicated by a blinded Clinical Endpoint Committee (CEC). The primary efficacy endpoint for both studies was the time to the first CEC-confirmed relapse.

In Study 1, the time to the first CEC-confirmed relapse was significantly longer in ENSPRYNG-treated patients compared to patients who received placebo (risk reduction 55%; hazard ratio 0.45; p = 0.0184). In the anti-AQP4 antibody positive population, there was a 74% risk reduction; hazard ratio 0.26; p = 0.0014 (Table 5; Figure 1). There was no evidence of a benefit in the anti-AQP4 antibody negative patients.

In Study 2, the time to the first CEC-confirmed relapse was significantly longer in patients treated with ENSPRYNG compared to patients who received placebo (risk reduction 62%; hazard ratio 0.38; p = 0.0184). In the anti-AQP4 antibody positive population, there was a 78% risk reduction; hazard ratio 0.22; p = 0.0143 (Table 5; Figure 2). There was no evidence of a benefit in the anti-AQP4 antibody negative patients.

Figure 1 Study 1: Time to First CEC-Determined NMOSD Relapse in the Randomized Controlled Period in the ITT Population Anti-AQP4 Antibody Positive Patients

Figure 2 Study 2: Time to First CEC-Determined NMOSD Relapse in the Randomized Controlled Period in the ITT Population Anti-AQP4 Antibody Positive Patients

ENSPRYNG is contraindicated in patients with:

• A known hypersensitivity to satralizumab or any of the inactive ingredients [see Warnings and Precautions (5.4)]
• Active Hepatitis B infection [see Warnings and Precautions (5.1)]
• Active or untreated latent tuberculosis [see Warnings and Precautions (5.1)]

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infections [see Warnings and Precautions (5.1)]
• Elevated Liver Enzymes [see Warnings and Precautions (5.2)]
• Decreased Neutrophil Counts [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

Read this Instructions for Use before you start using your prefilled syringe and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider will decide if you or a caregiver can give you injections of ENSPRYNG at home. They will also show you or a caregiver the correct and safe way to use the syringe before you use it for the first time.

Talk to your healthcare provider if you have any questions.

Important Information

• Each syringe is prefilled with a medicine called ENSPRYNG.
• Each carton of ENSPRYNG contains only 1 prefilled syringe.
• Each prefilled syringe can be used only 1 time.

Do not share your ENSPRYNG syringe with other people. You may give them a serious infection or get a serious infection from them.

Do not:

• take the needle cap off until you are ready to inject ENSPRYNG.
• use the syringe if it has been dropped or damaged.
• try to take the syringe apart at any time.
• leave the syringe unattended.
• re-use the same syringe.

How should I store the ENSPRYNG prefilled syringe?

• Keep the unused syringe in the refrigerator between 36°F to 46°F (2°C to 8°C) until ready to use.
• Before giving an injection, if the ENSPRYNG is not opened, it can be removed from and placed back in the refrigerator if needed. The total combined time out of the refrigerator should not be more than 8 days at a temperature that does not go above 86°F (30°C).
• Keep the syringe in its original carton away from direct sunlight.
• Always keep the syringe dry.

Keep the ENSPRYNG syringe and all medicines out of the reach of children.

Do not:

• freeze the syringe.
• use the syringe if it has been frozen.
• shake.

Supplies needed to give your injection

Each ENSPRYNG carton contains:

• 1 prefilled syringe for 1-time use only.

Not included in the carton:

• 1 alcohol pad
• 1 sterile cotton ball or gauze
• 1 small bandage
• 1 FDA-cleared puncture-resistant sharps container for safe disposal of the needle cap and used syringe. See Step 21 "Disposing of ENSPRYNG" at the end of this Instructions for Use.

ENSPRYNG prefilled syringe

(See Figure A and Figure B)

Before use:

After use:

The syringe has a needle-shield that automatically covers the needle when the injection is complete.

Prepare to use ENSPRYNG

• 1.
  Take the carton containing the syringe out of the refrigerator and place it on a clean, flat work surface (like a table).
• 2.
  Check the expiration (EXP) date on the back of the carton (See Figure C). Do not use if the carton has expired.
• 3.
  Check the front of the carton to make sure it is sealed (Figure C). Do not use if the seal has been broken.

If the expiration date has passed or the seal is broken, do not use. Then go to Step 21 "Disposing of ENSPRYNG" and contact your healthcare provider.

• 4.
  Open the sealed carton (See Figure D).

• 5.
  Carefully lift the syringe out of the carton by holding the barrel (See Figure E).
  
  Do not:
  • turn the carton upside down to remove the syringe.
  • touch the activation guards because this may damage the syringe.
  • hold the plunger or needle cap.

Check the syringe

(See Figure F)

• 6.
  Check the expiration date on the syringe. Do not use the syringe if it has expired.
• 7.
  Check the syringe for any damage. Do not use if it is cracked or broken.
• 8.
  Check that the liquid through the viewing window is clear and colorless to slightly yellow. Do not inject the medicine if the liquid is cloudy, discolored, or has particles in it.
  • There may be some small air bubbles in the syringe. This is normal and you should not try to remove them.

If the expiration (EXP) date has passed, the syringe is damaged or the liquid is cloudy, discolored or has particles in it, do not use. Then go to Step 21 "Disposing of ENSPRYNG" and contact your healthcare provider.

Let your syringe warm up

• 9.
  After you have checked the syringe, place it on a clean, flat work surface (like a table) for 30 minutes. This will allow it to reach room temperature. (See Figure G).
  
  It is important to let the syringe gently warm up as injecting cold medicine may feel uncomfortable and make it harder to push.
  
  Do not:
  • speed up the warming process in any way, such as using a microwave or placing the syringe in warm water.
  • remove the needle cover while the syringe is reaching room temperature.

Wash your hands

• 10.
  Wash your hands with soap and water. (See Figure H).

Choose the injection site

• 11.
  Choose your injection site in either:
  • the lower part of your stomach (abdomen) or
  • the front and middle of your thighs. (See Figure I).
    
    
    Figure I
  • Do not inject into the 2-inch (5 cm) area around your belly button.
  • Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or broken.

Choose a different injection site for each new injection. Choose a different place to inject which is at least 1 inch (2.5 cm) away from the place where you last injected.

Clean the injection site

• 12.
  Wipe the injection site with an alcohol pad and let it air dry.
  
  Do not:
  • fan or blow on the area which you have cleaned.
  • touch the injection site again before you give the injection.

Inject ENSPRYNG

• 13.
  Hold the barrel of the syringe between your thumb and index finger. With your other hand, pull the needle cap straight off. You may see a drop of liquid at the end of the needle. This is normal and will not affect your dose (See Figure K).
  • Use the syringe within 5 minutes of removing the cap or the needle may clog.
    
    Do not:
  • take the needle cap off until you are ready to inject ENSPRYNG.
  • put the needle cap back on after it has been removed as this may damage the needle.
  • touch the needle or let it touch any surfaces after removing the needle cap.

• 14.
  Throw away the needle cap in a puncture-resistant sharps container immediately. See Step 21 "Disposing of ENSPRYNG".
• 15.
  Hold the barrel of the syringe using your thumb and index finger. With your other hand, pinch the area of skin you have cleaned (See Figure L).
• 16.
  Use a quick, dart-like motion to insert the needle at an angle between 45° to 90°(See Figure L).
  
  Do not:
  • insert the needle through clothing.
  • change the angle of the injection.
  • insert the needle again.

• 17.
  After the needle is inserted, let go of the pinched skin.
• 18.
  Slowly inject all of the medicine by gently pushing the plunger all the way down until it touches the activation guards (See Figure M).
  Figure M
• 19.
  Gently release the plunger and allow the needle to come out of the skin at the same angle it was inserted (See Figure N).
  Figure N
  • The needle will now be covered by the needle-shield. If the needle is not covered, carefully place the syringe into a puncture-resistant sharps container to avoid injury. See Step 21 "Disposing of ENSPRYNG".

Taking care of the injection site

• 20.
  There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site but do not rub it. If needed, you may also cover the area you injected with a small bandage. If the medicine gets into contact with your skin, wash the area with water.

Disposing of ENSPRYNG

• 21.
  Put your used syringe in an FDA-cleared sharps disposal container immediately after use (See Figure O). Do not throw away (dispose of) the syringe in your household trash.
  Figure O
  • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
    • upright and stable during use
    • leak-resistant
    • properly labeled to warn of hazardous waste inside the container
  • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
  • Do not dispose of your used sharps disposal container in trash unless your community guidelines permit this.
  • Do not recycle your used sharps disposal container.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Genentech, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

U.S. License No.: 1048

Approved: 8/2020

ENSPRYNG^® is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

© 2020 Genentech, Inc. All rights reserved.

The relationship between any of the pharmacodynamic effects of ENSPRYNG and clinical outcomes in NMOSD is unknown.

The pharmacokinetics of ENSPRYNG have been characterized both in Japanese and Caucasian healthy volunteers, and in NMOSD patients. The pharmacokinetics in NMOSD patients using the recommended dose were characterized using population pharmacokinetic analysis methods based on a database of 154 patients.

The concentration-time course of ENSPRYNG in patients with NMOSD was accurately described by a two-compartment population pharmacokinetic model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order subcutaneous absorption. ENSPRYNG clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Body weight was shown to be a significant covariate, with clearance and V_c for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a patient weighing 60 kg.

Steady state pharmacokinetics were achieved after the loading period (8 weeks) as follows [mean (±SD)]: C_min: 19.7 (12.2) mcg/mL, C_max: 31.5 (14.9) mcg/mL, and AUC: 737 (386) mcg.mL/day.

For subcutaneous use only.

Prior to every use of ENSPRYNG, advise patients to consult with their healthcare professional (HCP) if they suspect an active infection, including localized infections. In case of active infection, delay use of ENSPRYNG until the infection is resolved [see Warnings and Precautions (5.1)].

The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks.

ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

The precise mechanism by which satralizumab-mwge exerts therapeutic effects in NMOSD is unknown but is presumed to involve inhibition of IL-6-mediated signaling through binding to soluble and membrane-bound IL-6 receptors.

• Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.
• Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed 8 days at a temperature that does not exceed 30°C (86°F).

• Infections: Delay ENSPRYNG administration in patients with an active infection until the infection is resolved. Vaccination with live or live-attenuated vaccines is not recommended during treatment. (5.1)
• Elevated Liver Enzymes: Monitor ALT and AST levels during treatment; interruption of ENSPRYNG may be required. (5.2)
• Decreased Neutrophil Counts: Monitor neutrophils during treatment. (5.3)

Mild and moderate elevations of liver enzymes have been observed in patients treated with ENSPRYNG at a higher incidence than in patients receiving placebo [see Adverse Reactions (6.1)].

ALT and AST levels should be monitored every 4 weeks for the first 3 months of treatment, followed by every 3 months for one year, and thereafter, as clinically indicated [see Dosage and Administration (2.4)].

• Hepatitis B virus, tuberculosis, and liver transaminase screening is required before the first dose. (2.1)
• Prior to every use, determine if there is an active infection. (2.2)
• The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks. (2.2)
• See Full Prescribing Information for important preparation and administration instructions. (2.3)

Injection: 120 mg/mL clear, and colorless to slightly yellow solution in single-dose prefilled syringe.

Hypersensitivity reactions, including rash, urticaria, and fatal anaphylaxis, have occurred with other interleukin-6 receptor antagonists.

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 reflect the rates observed in clinical practice.

The safety of ENSPRYNG was evaluated in two randomized, placebo-controlled clinical trials [Study 1 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study 2 evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 1 and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 2 [see Clinical Studies (14)]. In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately 2 years in Study 1 and approximately 3 years in Study 2. The median exposure time on placebo treatment was approximately 1 year in both Study 1 and Study 2.

Adverse reactions that occurred in Study 1 and Study 2 in more than 5% of patients treated with ENSPRYNG, and at a greater incidence than in patients who received placebo, are shown in Table 3 and Table 4, respectively. The most common adverse reactions (15% or greater with ENSPRYNG in either) were nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea.

Decreases in neutrophil counts were observed in patients treated with ENSPRYNG at a higher incidence than placebo [see Adverse Reactions (6.1)].

Neutrophil counts should be monitored 4 to 8 weeks after initiation of therapy, and thereafter at regular clinically determined intervals [see Dosage and Administration (2.4)].

Advise the patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of a health care professional (HCP). After proper training in subcutaneous injection technique, a patient may self-inject ENSPRYNG or the patient's caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate. See ENSPRYNG "Instructions for Use" (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG.
• Patients or caregivers should seek immediate medical attention if the patient develops symptoms of a serious allergic reaction and should not administer further doses until evaluated by a HCP [see Contraindications (4) and Warning and Precautions (5.4)].
• Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way.
• Inspect visually for particulate matter and discoloration prior to administration. ENSPRYNG solution should be clear and colorless to slightly yellow. Do not use ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged.
• Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU.
• Administer ENSPRYNG by subcutaneous injection in the abdomen or thigh. Rotate injection sites with each administration. Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

NDC 50242-007-01

Rx only

Enspryng^®

(satralizumab-mwge)

Injection

120 mg/mL

For Subcutaneous Use.

Single-Dose Prefilled Syringe.

Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.

Do not freeze. Do not shake.

ATTENTION PHARMACIST: Each patient is required to receive the enclosed

Medication Guide.

1 prefilled syringe

Genentech

10240933

Hepatitis B Virus Screening

Prior to initiating ENSPRYNG, perform Hepatitis B virus (HBV) screening. ENSPRYNG is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with ENSPRYNG [see Contraindications (4) and Warnings and Precautions (5.1)].

Satralizumab-mwge is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody based on a human IgG2 framework. Each light chain and heavy chain consists of 214 and 443 amino acids, respectively. Satralizumab-mwge is a glycoprotein with an approximate molecular weight of 143 kDa and is produced by recombinant DNA technology in Chinese hamster ovary cells. The binding of satralizumab-mwge to the IL-6 receptor is pH-sensitive.

ENSPRYNG (satralizumab-mwge) injection for subcutaneous administration is supplied as a sterile, clear, colorless to slightly yellow solution with no preservative with an approximate pH of 6. ENSPRYNG is supplied in a single-dose prefilled syringe. Each syringe delivers 1 mL of solution containing 120 mg of satralizumab-mwge, L-arginine (26.1 mg), L-histidine (3.1 mg), poloxamer 188 (0.5 mg), L-aspartic acid (pH adjustment), and Water for Injection, USP.

An increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG.

The most common infections reported in a randomized clinical trial of patients treated with ENSPRYNG who were not on other chronic immunosuppressant therapies (Study 1), and that occurred more often than in patients receiving placebo, were nasopharyngitis (12%) and cellulitis (10%). The most common infections in patients who were on an additional concurrent immunosuppressant, and that occurred more often than in patients receiving placebo, were nasopharyngitis (31%), upper respiratory infection (19%), and pharyngitis (12%).

Delay ENSPRYNG administration in patients with an active infection, including localized infections, until the infection is resolved.

ENSPRYNG (satralizumab-mwge) injection is available as a sterile, preservative-free, clear, colorless to slightly yellow solution in single-dose prefilled syringe (PFS) with needle safety device.

ENSPRYNG PFS is not made with natural rubber latex. Each ENSPRYNG carton contains one single-dose 120 mg/mL prefilled syringe (NDC 50242-007-01).

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of satralizumab-mwge [see Clinical Pharmacology (12.3)]. In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of anti-satralizumab-mwge antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In Study 1 and Study 2, anti-drug-antibodies (ADAs) were observed in 73% and 38% of patients receiving ENSPRYNG in the double-blind period, respectively. The ability of these ADAs to neutralize satralizumab-mwge binding is unknown. Patients with higher body weight and lower exposure were more likely to develop ADAs (irrespective of treatment with IST). Exposure was lower in ADA positive patients. Although anti-satralizumab-mwge antibody development was not found to affect the efficacy of ENSPRYNG in these patients, the available data are too limited to make definitive conclusions. Immunogenicity does not have a clinically-relevant impact on safety. Based on the available information, neither dose interruption nor modification is warranted in those patients who develop ADAs.

The efficacy of ENSPRYNG for the treatment of NMOSD in adult patients was established in two studies. Study 1 was a randomized (2:1), placebo-controlled trial in 95 patients without concurrent IST (Study 1, NCT02073279) in which 64 patients were anti-AQP4 antibody positive and 31 patients were anti-AQP4 antibody negative.

Study 2 was a randomized (1:1), placebo-controlled trial in 76 adult patients with concurrent IST (Study 2, NCT02028884). Of these, 52 adult patients were anti-AQP4 antibody positive and 24 adult patients were anti-AQP4 antibody negative.

Patients met the following eligibility criteria:

• Study 1: Clinical evidence of 1 relapse in the previous 12 months
• Study 2: Clinical evidence of at least 2 relapses in the previous 2 years, at least one of which must have occurred in the previous year
• EDSS score of 0 to 6.5 (both studies)
• Study 1: Patients were excluded if previously treated with IST within an interval specified for each such therapy
• Study 2: One of the following baseline treatments at a stable dose as a monotherapy for 8 weeks prior to baseline: azathioprine, mycophenolate mofetil, oral corticosteroids

In Study 1, 41 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 23 received placebo. Females accounted for 76% of the ENSPRYNG group and 96% of the placebo group. The remaining baseline demographic characteristics were balanced between the treatment groups. The mean age was 44 years. Fifty percent were White, 22% were Black or African-American, and 20% were Asian. The mean EDSS score was 3.8.

In Study 2, 26 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 26 received placebo. All patients were receiving either concurrent azathioprine (42%), oral corticosteroids (52%), or mycophenolate mofetil (6%) during the trial. The baseline demographic and disease characteristics were balanced between the treatment groups. Females accounted for 100% of the study population. Forty-six percent of patients were White and 52% were Asian. The mean age was 46 years. The mean EDSS score was 4.0.

All potential relapses were adjudicated by a blinded Clinical Endpoint Committee (CEC). The primary efficacy endpoint for both studies was the time to the first CEC-confirmed relapse.

In Study 1, the time to the first CEC-confirmed relapse was significantly longer in ENSPRYNG-treated patients compared to patients who received placebo (risk reduction 55%; hazard ratio 0.45; p = 0.0184). In the anti-AQP4 antibody positive population, there was a 74% risk reduction; hazard ratio 0.26; p = 0.0014 (Table 5; Figure 1). There was no evidence of a benefit in the anti-AQP4 antibody negative patients.

In Study 2, the time to the first CEC-confirmed relapse was significantly longer in patients treated with ENSPRYNG compared to patients who received placebo (risk reduction 62%; hazard ratio 0.38; p = 0.0184). In the anti-AQP4 antibody positive population, there was a 78% risk reduction; hazard ratio 0.22; p = 0.0143 (Table 5; Figure 2). There was no evidence of a benefit in the anti-AQP4 antibody negative patients.

Figure 1 Study 1: Time to First CEC-Determined NMOSD Relapse in the Randomized Controlled Period in the ITT Population Anti-AQP4 Antibody Positive Patients

Figure 2 Study 2: Time to First CEC-Determined NMOSD Relapse in the Randomized Controlled Period in the ITT Population Anti-AQP4 Antibody Positive Patients

ENSPRYNG is contraindicated in patients with:

• A known hypersensitivity to satralizumab or any of the inactive ingredients [see Warnings and Precautions (5.4)]
• Active Hepatitis B infection [see Warnings and Precautions (5.1)]
• Active or untreated latent tuberculosis [see Warnings and Precautions (5.1)]

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infections [see Warnings and Precautions (5.1)]
• Elevated Liver Enzymes [see Warnings and Precautions (5.2)]
• Decreased Neutrophil Counts [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

Read this Instructions for Use before you start using your prefilled syringe and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider will decide if you or a caregiver can give you injections of ENSPRYNG at home. They will also show you or a caregiver the correct and safe way to use the syringe before you use it for the first time.

Talk to your healthcare provider if you have any questions.

Important Information

• Each syringe is prefilled with a medicine called ENSPRYNG.
• Each carton of ENSPRYNG contains only 1 prefilled syringe.
• Each prefilled syringe can be used only 1 time.

Do not share your ENSPRYNG syringe with other people. You may give them a serious infection or get a serious infection from them.

Do not:

• take the needle cap off until you are ready to inject ENSPRYNG.
• use the syringe if it has been dropped or damaged.
• try to take the syringe apart at any time.
• leave the syringe unattended.
• re-use the same syringe.

How should I store the ENSPRYNG prefilled syringe?

• Keep the unused syringe in the refrigerator between 36°F to 46°F (2°C to 8°C) until ready to use.
• Before giving an injection, if the ENSPRYNG is not opened, it can be removed from and placed back in the refrigerator if needed. The total combined time out of the refrigerator should not be more than 8 days at a temperature that does not go above 86°F (30°C).
• Keep the syringe in its original carton away from direct sunlight.
• Always keep the syringe dry.

Keep the ENSPRYNG syringe and all medicines out of the reach of children.

Do not:

• freeze the syringe.
• use the syringe if it has been frozen.
• shake.

Supplies needed to give your injection

Each ENSPRYNG carton contains:

• 1 prefilled syringe for 1-time use only.

Not included in the carton:

• 1 alcohol pad
• 1 sterile cotton ball or gauze
• 1 small bandage
• 1 FDA-cleared puncture-resistant sharps container for safe disposal of the needle cap and used syringe. See Step 21 "Disposing of ENSPRYNG" at the end of this Instructions for Use.

ENSPRYNG prefilled syringe

(See Figure A and Figure B)

Before use:

After use:

The syringe has a needle-shield that automatically covers the needle when the injection is complete.

Prepare to use ENSPRYNG

• 1.
  Take the carton containing the syringe out of the refrigerator and place it on a clean, flat work surface (like a table).
• 2.
  Check the expiration (EXP) date on the back of the carton (See Figure C). Do not use if the carton has expired.
• 3.
  Check the front of the carton to make sure it is sealed (Figure C). Do not use if the seal has been broken.

If the expiration date has passed or the seal is broken, do not use. Then go to Step 21 "Disposing of ENSPRYNG" and contact your healthcare provider.

• 4.
  Open the sealed carton (See Figure D).

• 5.
  Carefully lift the syringe out of the carton by holding the barrel (See Figure E).
  
  Do not:
  • turn the carton upside down to remove the syringe.
  • touch the activation guards because this may damage the syringe.
  • hold the plunger or needle cap.

Check the syringe

(See Figure F)

• 6.
  Check the expiration date on the syringe. Do not use the syringe if it has expired.
• 7.
  Check the syringe for any damage. Do not use if it is cracked or broken.
• 8.
  Check that the liquid through the viewing window is clear and colorless to slightly yellow. Do not inject the medicine if the liquid is cloudy, discolored, or has particles in it.
  • There may be some small air bubbles in the syringe. This is normal and you should not try to remove them.

If the expiration (EXP) date has passed, the syringe is damaged or the liquid is cloudy, discolored or has particles in it, do not use. Then go to Step 21 "Disposing of ENSPRYNG" and contact your healthcare provider.

Let your syringe warm up

• 9.
  After you have checked the syringe, place it on a clean, flat work surface (like a table) for 30 minutes. This will allow it to reach room temperature. (See Figure G).
  
  It is important to let the syringe gently warm up as injecting cold medicine may feel uncomfortable and make it harder to push.
  
  Do not:
  • speed up the warming process in any way, such as using a microwave or placing the syringe in warm water.
  • remove the needle cover while the syringe is reaching room temperature.

Wash your hands

• 10.
  Wash your hands with soap and water. (See Figure H).

Choose the injection site

• 11.
  Choose your injection site in either:
  • the lower part of your stomach (abdomen) or
  • the front and middle of your thighs. (See Figure I).
    
    
    Figure I
  • Do not inject into the 2-inch (5 cm) area around your belly button.
  • Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or broken.

Choose a different injection site for each new injection. Choose a different place to inject which is at least 1 inch (2.5 cm) away from the place where you last injected.

Clean the injection site

• 12.
  Wipe the injection site with an alcohol pad and let it air dry.
  
  Do not:
  • fan or blow on the area which you have cleaned.
  • touch the injection site again before you give the injection.

Inject ENSPRYNG

• 13.
  Hold the barrel of the syringe between your thumb and index finger. With your other hand, pull the needle cap straight off. You may see a drop of liquid at the end of the needle. This is normal and will not affect your dose (See Figure K).
  • Use the syringe within 5 minutes of removing the cap or the needle may clog.
    
    Do not:
  • take the needle cap off until you are ready to inject ENSPRYNG.
  • put the needle cap back on after it has been removed as this may damage the needle.
  • touch the needle or let it touch any surfaces after removing the needle cap.

• 14.
  Throw away the needle cap in a puncture-resistant sharps container immediately. See Step 21 "Disposing of ENSPRYNG".
• 15.
  Hold the barrel of the syringe using your thumb and index finger. With your other hand, pinch the area of skin you have cleaned (See Figure L).
• 16.
  Use a quick, dart-like motion to insert the needle at an angle between 45° to 90°(See Figure L).
  
  Do not:
  • insert the needle through clothing.
  • change the angle of the injection.
  • insert the needle again.

• 17.
  After the needle is inserted, let go of the pinched skin.
• 18.
  Slowly inject all of the medicine by gently pushing the plunger all the way down until it touches the activation guards (See Figure M).
  Figure M
• 19.
  Gently release the plunger and allow the needle to come out of the skin at the same angle it was inserted (See Figure N).
  Figure N
  • The needle will now be covered by the needle-shield. If the needle is not covered, carefully place the syringe into a puncture-resistant sharps container to avoid injury. See Step 21 "Disposing of ENSPRYNG".

Taking care of the injection site

• 20.
  There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site but do not rub it. If needed, you may also cover the area you injected with a small bandage. If the medicine gets into contact with your skin, wash the area with water.

Disposing of ENSPRYNG

• 21.
  Put your used syringe in an FDA-cleared sharps disposal container immediately after use (See Figure O). Do not throw away (dispose of) the syringe in your household trash.
  Figure O
  • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is:
    • made of a heavy-duty plastic
    • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
    • upright and stable during use
    • leak-resistant
    • properly labeled to warn of hazardous waste inside the container
  • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.
  • Do not dispose of your used sharps disposal container in trash unless your community guidelines permit this.
  • Do not recycle your used sharps disposal container.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Genentech, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

U.S. License No.: 1048

Approved: 8/2020

ENSPRYNG^® is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

© 2020 Genentech, Inc. All rights reserved.

The relationship between any of the pharmacodynamic effects of ENSPRYNG and clinical outcomes in NMOSD is unknown.

The pharmacokinetics of ENSPRYNG have been characterized both in Japanese and Caucasian healthy volunteers, and in NMOSD patients. The pharmacokinetics in NMOSD patients using the recommended dose were characterized using population pharmacokinetic analysis methods based on a database of 154 patients.

The concentration-time course of ENSPRYNG in patients with NMOSD was accurately described by a two-compartment population pharmacokinetic model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order subcutaneous absorption. ENSPRYNG clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Body weight was shown to be a significant covariate, with clearance and V_c for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a patient weighing 60 kg.

Steady state pharmacokinetics were achieved after the loading period (8 weeks) as follows [mean (±SD)]: C_min: 19.7 (12.2) mcg/mL, C_max: 31.5 (14.9) mcg/mL, and AUC: 737 (386) mcg.mL/day.

For subcutaneous use only.

Prior to every use of ENSPRYNG, advise patients to consult with their healthcare professional (HCP) if they suspect an active infection, including localized infections. In case of active infection, delay use of ENSPRYNG until the infection is resolved [see Warnings and Precautions (5.1)].

The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks.

ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

The precise mechanism by which satralizumab-mwge exerts therapeutic effects in NMOSD is unknown but is presumed to involve inhibition of IL-6-mediated signaling through binding to soluble and membrane-bound IL-6 receptors.

• Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.
• Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed 8 days at a temperature that does not exceed 30°C (86°F).

• Infections: Delay ENSPRYNG administration in patients with an active infection until the infection is resolved. Vaccination with live or live-attenuated vaccines is not recommended during treatment. (5.1)
• Elevated Liver Enzymes: Monitor ALT and AST levels during treatment; interruption of ENSPRYNG may be required. (5.2)
• Decreased Neutrophil Counts: Monitor neutrophils during treatment. (5.3)

Mild and moderate elevations of liver enzymes have been observed in patients treated with ENSPRYNG at a higher incidence than in patients receiving placebo [see Adverse Reactions (6.1)].

ALT and AST levels should be monitored every 4 weeks for the first 3 months of treatment, followed by every 3 months for one year, and thereafter, as clinically indicated [see Dosage and Administration (2.4)].

• Hepatitis B virus, tuberculosis, and liver transaminase screening is required before the first dose. (2.1)
• Prior to every use, determine if there is an active infection. (2.2)
• The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks. (2.2)
• See Full Prescribing Information for important preparation and administration instructions. (2.3)

Injection: 120 mg/mL clear, and colorless to slightly yellow solution in single-dose prefilled syringe.

Hypersensitivity reactions, including rash, urticaria, and fatal anaphylaxis, have occurred with other interleukin-6 receptor antagonists.

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 reflect the rates observed in clinical practice.

The safety of ENSPRYNG was evaluated in two randomized, placebo-controlled clinical trials [Study 1 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study 2 evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 1 and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 2 [see Clinical Studies (14)]. In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately 2 years in Study 1 and approximately 3 years in Study 2. The median exposure time on placebo treatment was approximately 1 year in both Study 1 and Study 2.

Adverse reactions that occurred in Study 1 and Study 2 in more than 5% of patients treated with ENSPRYNG, and at a greater incidence than in patients who received placebo, are shown in Table 3 and Table 4, respectively. The most common adverse reactions (15% or greater with ENSPRYNG in either) were nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea.

Decreases in neutrophil counts were observed in patients treated with ENSPRYNG at a higher incidence than placebo [see Adverse Reactions (6.1)].

Neutrophil counts should be monitored 4 to 8 weeks after initiation of therapy, and thereafter at regular clinically determined intervals [see Dosage and Administration (2.4)].

Advise the patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of a health care professional (HCP). After proper training in subcutaneous injection technique, a patient may self-inject ENSPRYNG or the patient's caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate. See ENSPRYNG "Instructions for Use" (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG.
• Patients or caregivers should seek immediate medical attention if the patient develops symptoms of a serious allergic reaction and should not administer further doses until evaluated by a HCP [see Contraindications (4) and Warning and Precautions (5.4)].
• Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way.
• Inspect visually for particulate matter and discoloration prior to administration. ENSPRYNG solution should be clear and colorless to slightly yellow. Do not use ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged.
• Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU.
• Administer ENSPRYNG by subcutaneous injection in the abdomen or thigh. Rotate injection sites with each administration. Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

NDC 50242-007-01

Rx only

Enspryng^®

(satralizumab-mwge)

Injection

120 mg/mL

For Subcutaneous Use.

Single-Dose Prefilled Syringe.

Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.

Do not freeze. Do not shake.

ATTENTION PHARMACIST: Each patient is required to receive the enclosed

Medication Guide.

1 prefilled syringe

Genentech

10240933