Benlysta Injection, Powder, Lyophilized, For Solution

BENLYSTA is indicated for the treatment of patients 5 years of age and older with:

1. •Active systemic lupus erythematosus (SLE) who are receiving standard therapy, and
2. •Active lupus nephritis who are receiving standard therapy.

Limitations of Use

The efficacy of BENLYSTA has not been evaluated in patients with severe active central nervous system (CNS) lupus. Use of BENLYSTA is not recommended in this situation.

BENLYSTA is contraindicated in patients with a prior history of:

1. •Anaphylaxis with belimumab [see Warnings and Precautions (5.2)].
2. •Stevens-Johnson syndrome or toxic epidermal necrolysis with belimumab [see Warnings and Precautions (5.3)].

The following serious adverse reactions are described below and in the Warnings and Precautions section:

1. •Serious Infections [see Warnings and Precautions (5.1)]
2. •Hypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions (5.2)]
3. •Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions (5.3)]
4. •Depression and Suicidality [see Warnings and Precautions (5.4)]
5. •Malignancy [see Warnings and Precautions (5.5)]

• Serious Infections: Serious and sometimes fatal infections have occurred in patients receiving immunosuppressive agents, including BENLYSTA. Use with caution in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA if patients develop a new infection during treatment with BENLYSTA. (5.1)

• Progressive Multifocal Leukoencephalopathy (PML): Evaluate patients with new-onset or deteriorating neurological signs and symptoms for PML. If PML is suspected, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued. (5.1)

• Hypersensitivity Reactions, including Anaphylaxis: Serious and fatal reactions have been reported. (5.2)

• Stevens‑Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN): Discontinue BENLYSTA immediately if signs or symptoms of SJS/TEN occur. (5.3)

• Depression and Suicidality: Depression and suicidality were reported in trials with BENLYSTA. Assess for depression and risk of suicide before treatment with BENLYSTA and monitor during treatment. Instruct patients to contact their healthcare provider if new or worsening depression, suicidal thoughts, or other mood changes occur. (5.4)

• Immunization: Live vaccines should not be given concurrently with BENLYSTA. (5.6) 5.1 Serious Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Overall, the incidence of serious infections in controlled trials was similar in subjects receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in subjects receiving BENLYSTA [see Adverse Reactions (6.1)].

Consider the risk and benefit before initiating treatment with BENLYSTA in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while receiving it and monitor these patients closely.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with suspected PML, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued. 5.2 Hypersensitivity Reactions, including Anaphylaxis

Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported in association with BENLYSTA [see Adverse Reactions (6.1)]. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.

Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion-related reactions in all cases. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, some subjects (13%) received premedication, which may have mitigated or masked a hypersensitivity response or infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions or infusion-related reaction.

BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis and infusion-related reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion-related reactions. In the event of a serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. With intravenous administration, the infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration (2.1, 2.2)].

Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur. 5.3 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with BENLYSTA. Monitor for and advise patients about signs and symptoms of SJS/TEN during treatment with BENLYSTA. Discontinue BENLYSTA immediately if signs or symptoms suggestive of SJS/TEN occur. Early consultation with a dermatologist or other appropriate specialist is recommended to ensure greater diagnostic accuracy and appropriate management. If the etiology is considered to be associated with BENLYSTA, permanently discontinue and do not reintroduce BENLYSTA [see Contraindications (4)]. 5.4 Depression and Suicidality

In controlled clinical trials, depression and suicidality were reported in subjects receiving BENLYSTA [see Adverse Reactions (6.1)]. Assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with BENLYSTA and continue to monitor patients during treatment. Instruct patients receiving BENLYSTA (and caregivers, if applicable) to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or other mood changes. Consider the risk and benefit of continued treatment with BENLYSTA for patients who develop such symptoms. 5.5 Malignancy

There is an increased risk of malignancies with the use of immunosuppressants. The impact of treatment with BENLYSTA on the development of malignancies is not known [see Adverse Reactions (6.1)].

Consider the individual benefit-risk in patients with known risk factors for the development or reoccurrence of malignancy prior to prescribing BENLYSTA. In patients who develop malignancies, consider the risk and benefit of continued treatment with BENLYSTA. 5.6 Immunization

Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations. Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. 5.7 Concomitant Use with Other Biologic Therapies

Available data do not support the safety and efficacy of concomitant use of BENLYSTA with rituximab in patients with SLE. An increased incidence of serious infections and post-injection systemic reactions in subjects receiving BENLYSTA concomitantly with rituximab compared to subjects receiving BENLYSTA alone has been observed [see Adverse Reactions (6.1)]. The safety and efficacy of BENLYSTA concomitantly with other biologic therapies, including B-cell-targeted therapies, have not been established. Caution should be exercised if BENLYSTA is administered in combination with other biologic therapies [see Warnings and Precautions (5)].

BENLYSTA for intravenous use must be reconstituted and diluted prior to administration. Do not administer as an intravenous push or bolus.

Recommended Dosage and Administration

The recommended intravenous BENLYSTA dosage in patients 5 years of age and older with active SLE or lupus nephritis is 10 mg/kg at 2‑week intervals for the first 3 doses and at 4‑week intervals thereafter.

Reconstitute, dilute, and administer as an intravenous infusion over a period of 1 hour. Do not concomitantly infuse BENLYSTA in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of BENLYSTA with other agents.

The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. The infusion must be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Contraindications (4), Warnings and Precautions (5.2)].

Preparation of the Intravenous Solution

BENLYSTA for intravenous use is provided as a lyophilized powder in a single‑dose vial and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows. Use of a 21- to 25-gauge needle is recommended when piercing the vial stopper for reconstitution and dilution.

Reconstitution Instructions for Intravenous Use:

1. 1.Remove the vial of BENLYSTA from the refrigerator and allow to stand for 10 to 15 minutes for the vial to reach room temperature.
2. 2.Reconstitute the BENLYSTA powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain a concentration of 80 mg/mL belimumab.
3. •Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.
4. •Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.
5. 3.Direct the stream of sterile water towards the side of the vial to minimize foaming. Gently swirl the vial for 60 seconds. Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved. Do not shake. Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes. Protect the reconstituted solution from sunlight.
6. 4.If a mechanical reconstitution device (swirler) is used to reconstitute BENLYSTA, do not exceed 500 rpm or swirl the vial for more than 30 minutes.
7. 5.Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles. Small air bubbles, however, are expected and acceptable.

Dilution Instructions for Intravenous Use:

1. 1.Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should only be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), 0.45% Sodium Chloride Injection, USP (half-normal saline), or Lactated Ringer’s Injection, USP to a volume of 250 mL for intravenous infusion. To prepare the intravenous infusion solution for patients whose body weight is less than or equal to 40 kg, a 100 mL bag or bottle of normal saline, half-normal saline, or Lactated Ringer’s Injection may be used such that the resulting belimumab concentration in the infusion bag does not exceed 4 mg/mL. From a 250‑mL (or 100‑mL) infusion bag or bottle of normal saline, half-normal saline, or Lactated Ringer’s Injection, withdraw and discard a volume equal to the volume of the reconstituted solution of BENLYSTA required for the patient’s dose. Then add the required volume of the reconstituted solution of BENLYSTA into the intravenous infusion solution in the infusion bag or bottle. Gently invert the bag or bottle to mix the intravenous infusion solution. Any unused solution in the vials must be discarded.
2. 2.Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed.
3. 3.If the reconstituted solution of BENLYSTA is not used immediately, store, protect from direct sunlight and refrigerate at 36°F to 46°F (2°C to 8°C). Store solutions of BENLYSTA diluted in normal saline, half‑normal saline, or Lactated Ringer’s Injection at 36°F to 46°F (2°C to 8°C) or room temperature. The total time from reconstitution of BENLYSTA to completion of infusion should not exceed 8 hours.
4. 4.No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags have been observed.

The recommended subcutaneous BENLYSTA dosage in patients 5 years of age and older with active SLE or lupus nephritis is provided in Table 1. Administer BENLYSTA subcutaneously in the abdomen or thigh. For patients less than 10 years of age, BENLYSTA must be administered by a healthcare professional or trained caregiver.

Administration Instructions for Subcutaneous Injection

1. 1.Administer the first subcutaneous injection of BENLYSTA under the supervision of a healthcare provider. Provide patients or caregivers with proper training on subcutaneous administration and education about signs and symptoms of hypersensitivity reactions [see Warnings and Precautions (5.2)]. For adults and pediatric patients 10 years of age and older, subsequent subcutaneous BENLYSTA administrations may be performed by the patient or trained caregiver, if determined to be appropriate. For pediatric patients less than 10 years of age, subsequent subcutaneous BENLYSTA administrations must be performed by a healthcare provider or trained caregiver.
2. 2.Instruct the patient or caregiver to follow the directions for administration provided in the Instructions for Use.
3. 3.Instruct the patient or caregiver to remove the autoinjector or prefilled syringe from the refrigerator and allow it to sit at room temperature for 30 minutes prior to the subcutaneous injection. Do not warm BENLYSTA in any other way.
4. 4.Prior to administration, instruct the patient or caregiver to visually inspect the window of the autoinjector or the prefilled syringe for particulate matter or discoloration. BENLYSTA should be clear to opalescent and colorless to pale yellow. Do not use BENLYSTA if the product exhibits discoloration or particulate matter. Instruct the patient or caregiver not to use the BENLYSTA autoinjector or prefilled syringe if dropped on a hard surface.
5. 5.When injecting in the same body region, advise the patient or caregiver to use a different injection site for each injection; never give injections into areas where the skin is tender, bruised, red, or hard. When administering a 400‑mg dose, inject each 200‑mg injection at least 5 cm (approximately 2 inches) apart.
6. 6.Instruct the patient or caregiver to administer BENLYSTA, preferably on the same day each week or the same day of alternate weeks, as appropriate.
7. 7.If a dose is missed, instruct the patient or caregiver to administer a dose as soon as the patient remembers. Thereafter, the patient can resume dosing on their usual day of administration or start a new schedule from the day that the missed dose was administered.

Intravenous Infusion

For injection: 120 mg or 400 mg of belimumab as a lyophilized powder in single‑dose vials for reconstitution and dilution prior to intravenous infusion.

Subcutaneous Injection

Injection: 200 mg/mL of belimumab as a clear to opalescent and colorless to pale yellow solution in a single-dose prefilled autoinjector or a single-dose prefilled glass syringe.

Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, cyclophosphamide, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG‑CoA reductase inhibitors (statins), and/or non-steroidal anti-inflammatory drugs (NSAIDs) without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Clinical Pharmacology (12.3)].