Benlysta
Generic Name: belimumab
Dosage Form: injection, powder, lyophilized, for solution
Indications and Usage for Benlysta
Benlysta
(belimumab) is indicated for the treatment of adult patients with active,
autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving
standard therapy.
Limitations of Use
The
efficacy of Benlysta has not been evaluated in patients with severe active lupus
nephritis or severe active central nervous system lupus. Benlysta has not been
studied in combination with other biologics or intravenous cyclophosphamide.
Use of Benlysta is not recommended in these situations.
SLIDESHOW
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Benlysta Dosage and Administration
Benlysta may be administered as an intravenous infusion or as a
subcutaneous injection. Vials are intended for intravenous use only (not for
subcutaneous use) and autoinjectors and prefilled syringes are intended for
subcutaneous use only (not for intravenous use).
Intravenous Preparation and Dosing Instructions
Recommended Intravenous Dosage Regimen
Benlysta
for intravenous use must be reconstituted and diluted prior to administration.
Do not administer as an intravenous push or bolus.
The
recommended intravenous dosage regimen 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. 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 (5.3)].
Premedication Recommendations prior to Intravenous Use
Prior to
intravenous dosing with Benlysta, consider administering premedication for
prophylaxis against infusion reactions and hypersensitivity reactions [see
Warnings and Precautions (5.3, 5.4), Adverse
Reactions (6.1)].
Preparation of Intravenous Solutions
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.
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.
Reconstitute
the Benlysta powder with Sterile Water for Injection, USP, as follows. The
reconstituted solution will contain a concentration of 80 mg/mL belimumab.
•
Reconstitute
the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.
•
Reconstitute
the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.
3.
The
stream of sterile water should be directed toward 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.
4.
If a
mechanical reconstitution device (swirler) is used to reconstitute Benlysta, it
should not exceed 500 rpm and the vial swirled for no longer than 30
minutes.
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:
6.
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.
From a 250‑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
infusion bag or bottle. Gently invert the bag or bottle to mix the solution.
Any unused solution in the vials must be discarded.
7.
Parenteral
drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Discard the solution if any particulate matter or discoloration is observed.
8.
The
reconstituted solution of Benlysta, if not used immediately, should be stored
protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F).
Solutions of Benlysta diluted in normal saline, half-normal saline, or Lactated
Ringer’s Injection may be stored at 2° to 8°C (36° to 46°F) or room
temperature. The total time from reconstitution of Benlysta to completion of
infusion should not exceed 8 hours.
9.
No
incompatibilities between Benlysta and polyvinylchloride or polyolefin bags
have been observed
Administration Instructions for Intravenous Use
1.
The
diluted solution of Benlysta should be administered by intravenous infusion,
over a period of 1 hour.
2.
Benlysta
should be administered by healthcare providers prepared to manage
anaphylaxis [see Warnings and Precautions (5.3)].
3.
Benlysta
should not be infused concomitantly 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.
2.2 Subcutaneous
Dosing Instructions
Recommended Subcutaneous Dosage
Regimen
The recommended dosage is 200 mg once weekly
given as a subcutaneous injection in the abdomen or thigh. Subcutaneous dosing
is not based on weight.
If transitioning from intravenous therapy with
Benlysta to subcutaneous administration, administer the first subcutaneous dose
1 to 4 weeks after the last intravenous dose.
Administration Instructions for Subcutaneous
Injection
1.
It is recommended that the first subcutaneous
injection of Benlysta should be under the supervision of a healthcare
professional. The healthcare provider should provide proper training in
subcutaneous technique and education about signs and symptoms of
hypersensitivity reactions [see Warning and Precautions (5.3)]. A patient may self-inject or the patient caregiver
may administer Benlysta subcutaneously after the healthcare provider determines
it is appropriate.
2.
Instruct the patient or patient caregiver to follow
the directions for administration provided in the Instructions for Use.
3.
Instruct the patient 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.
Prior to administration, instruct the patient or
patient 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 not
to use the Benlysta autoinjector or prefilled syringe if dropped on a hard
surface.
5.
When injecting in the same body region, advise the
patient to use a different injection site each week; never give injections into
areas where the skin is tender, bruised, red, or hard.
6.
Instruct the patient to administer Benlysta
200 mg once a week, preferably on the same day each week.
7.
If a dose is missed, instruct the patient 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 weekly
schedule from the day that the missed dose was administered. It is not
recommended to administer 2 doses on the same day.
Dosage Forms and Strengths
Intravenous Infusion
For injection: 120 mg or 400 mg lyophilized powder in
single‑dose vials for reconstitution and dilution prior to intravenous
infusion.
Subcutaneous Injection
Injection: 200 mg/mL as a clear to opalescent and colorless
to pale yellow solution in a single-dose prefilled autoinjector or a
single-dose prefilled glass syringe.
Contraindications
Benlysta is contraindicated in patients who have had anaphylaxis
with belimumab.
Warnings and Precautions
Mortality
There were more deaths reported with Benlysta than with placebo
during the controlled period of the intravenous clinical trials. Out of 2,133
patients in 3 clinical trials, a total of 14 deaths occurred during the
placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%),
0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, Benlysta 1
mg/kg, Benlysta 4 mg/kg, and Benlysta 10 mg/kg, respectively. No single cause
of death predominated. Etiologies included infection, cardiovascular disease,
and suicide
In the controlled trial of Benlysta administered subcutaneously
(N = 836), a total of 5 deaths occurred during the
placebo-controlled, double-blind treatment period (0.7% [2/280] of patients
receiving placebo and 0.5% [3/556] of patients receiving Benlysta). Infection
was the most common cause of death.
Serious Infections
Serious
and sometimes fatal infections have been reported in patients receiving
immunosuppressive agents, including Benlysta. Physicians should exercise
caution when considering the use of Benlysta in patients with severe or chronic
infections. Consider interrupting therapy with Benlysta in patients who develop
a new infection while undergoing treatment with Benlysta and monitor these
patients closely.
In the
controlled clinical trials of Benlysta administered intravenously, the overall
incidence of infections was 71% in patients treated with Benlysta compared with
67% in patients who received placebo. The most frequent infections (>5% of
patients receiving Benlysta) were upper respiratory tract infection, urinary
tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious
infections occurred in 6.0% of patients treated with Benlysta and in 5.2% of
patients who received placebo. The most frequent serious infections included
pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections
leading to discontinuation of treatment occurred in 0.7% of patients receiving
Benlysta and 1.0% of patients receiving placebo. Infections resulting in death
occurred in 0.3% (4/1,458) of patients treated with Benlysta and in 0.1%
(1/675) of patients receiving placebo.
In the controlled trial of Benlysta administered subcutaneously
(N = 836), the overall incidence of infections was 55% in patients
treated with Benlysta compared with 57% in patients who received placebo
(serious infections: 4.1% with Benlysta and 5.4% with placebo). The most
commonly reported infections with Benlysta administered subcutaneously were
similar to those reported with Benlysta administered intravenously.
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 confirmed PML,
consider stopping immunosuppressant therapy, including Benlysta.
Hypersensitivity Reactions, including Anaphylaxis
Acute
hypersensitivity reactions, including anaphylaxis and death, have been reported
in association with Benlysta. 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.
In the
controlled clinical trials of Benlysta administered intravenously,
hypersensitivity reactions (occurring on the same day of infusion) were
reported in 13% (191/1,458) of patients receiving Benlysta and 11% (76/675) of
patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of
patients receiving Benlysta and 0.4% (3/675) of patients receiving placebo.
Manifestations included hypotension, angioedema, urticaria or other rash,
pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not
possible to distinguish between hypersensitivity reactions and infusion
reactions in all cases [see Warnings and Precautions
(5.4)]. Some patients (13%) received premedication, which may
have mitigated or masked a hypersensitivity response; however, there is
insufficient evidence to determine whether premedication diminishes the
frequency or severity of hypersensitivity reactions.
Benlysta
for intravenous use should be administered by healthcare providers prepared to
manage anaphylaxis. In the event of a serious reaction, administration of
Benlysta must be discontinued immediately and appropriate medical therapy
administered. Patients should be monitored during and for an appropriate period
of time after intravenous administration of Benlysta.
In the controlled trial of Benlysta administered subcutaneously
(N = 836), systemic hypersensitivity reactions were similar to those
observed in the intravenous clinical trials.
Patients
receiving Benlysta should be informed of the signs and symptoms of
hypersensitivity reactions and be instructed to seek immediate medical care
should a reaction occur.
Infusion Reactions
In the
controlled clinical trials of Benlysta administered intravenously, adverse
events associated with the infusion (occurring on the same day of the infusion)
were reported in 17% (251/1,458) of patients receiving Benlysta and 15%
(99/675) of patients receiving placebo. Serious infusion reactions (excluding
hypersensitivity reactions) were reported in 0.5% of patients receiving
Benlysta and 0.4% of patients receiving placebo and included bradycardia,
myalgia, headache, rash, urticaria, and hypotension. The most common infusion
reactions (≥3% of patients receiving Benlysta) were headache, nausea, and skin
reactions. Due to overlap in signs and symptoms, it was not possible to
distinguish between hypersensitivity reactions and infusion reactions in all
cases [see Warnings and Precautions (5.3)].
Some patients (13%) received premedication, which may have mitigated or masked
an infusion reaction; however, there is insufficient evidence to determine
whether premedication diminishes the frequency or severity of infusion
reactions [see Adverse Reactions (6.1)]
Benlysta
for intravenous use should be administered by healthcare providers prepared to
manage infusion reactions. The infusion rate may be slowed or interrupted if
the patient develops an infusion reaction. Healthcare providers should be aware
of the risk of hypersensitivity reactions, which may present as infusion
reactions, and monitor patients closely.
Depression
In the
controlled clinical trials of Benlysta administered intravenously, psychiatric
events were reported more frequently with Benlysta (16%) than with placebo
(12%), related primarily to depression-related events (6.3% Benlysta and 4.7%
placebo), insomnia (6.0% Benlysta and 5.3% placebo), and anxiety (3.9% Benlysta
and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients
receiving Benlysta (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4%
of patients receiving placebo. Serious depression was reported in 0.4%
(6/1,458) of patients receiving Benlysta and 0.1% (1/675) of patients receiving
placebo. Two suicides (0.1%) were reported in patients receiving Benlysta.
In the controlled trial of Benlysta administered subcutaneously
(N = 836), psychiatric events were reported in 6% of patients treated
with Benlysta and in 11% of patients who received placebo. Depression-related
events were reported in 2.7% of patients receiving Benlysta and 3.6% of
patients receiving placebo. Serious psychiatric events were reported in 0.2% of
patients receiving Benlysta and in no patients receiving placebo. There were no
serious depression-related events or suicides reported in either group.
The
majority of patients who reported serious depression or suicidal behavior had a
history of depression or other serious psychiatric disorders and most were
receiving psychoactive medications. It is unknown if treatment with Benlysta is
associated with increased risk for these events.
Patients
receiving Benlysta should be instructed to contact their healthcare provider if
they experience new or worsening depression, suicidal thoughts, or other mood
changes.
Malignancy
The
impact of treatment with Benlysta on the development of malignancies is not
known.
In the controlled clinical trials of Benlysta administered
intravenously, malignancies (including non-melanoma skin cancers) were reported
in 0.4% of patients receiving Benlysta and 0.4% of patients receiving placebo.
In the intravenous controlled clinical trials, malignancies, excluding
non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of
patients receiving Benlysta and placebo, respectively. In the controlled
clinical trial of Benlysta administered subcutaneously (N = 836), the
data were similar. The mechanism of action of Benlysta could increase the risk
for the development of malignancies.
Immunization
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.
Because of its mechanism of action, Benlysta may interfere with the response to
immunizations.
Concomitant Use with Other Biologic Therapies or
Intravenous Cyclophosphamide
Benlysta
has not been studied in combination with other biologic therapies, including
B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of
Benlysta is not recommended in combination with biologic therapies or
intravenous cyclophosphamide.
Adverse Reactions
The
following have been observed with Benlysta and are discussed in detail in the
Warnings and Precautions section:
•
Mortality [see Warnings
and Precautions (5.1)]
•
Serious Infections [see Warnings
and Precautions (5.2)]
•
Hypersensitivity Reactions, including Anaphylaxis [see Warnings
and Precautions (5.3)]
•
Infusion Reactions [see Warnings and Precautions (5.4)]
•
Depression [see Warnings
and Precautions (5.5)]
•
Malignancy [see Warnings
and Precautions (5.6)]
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared with rates in the clinical trials of another drug
and may not reflect the rates observed in practice
Clinical Trials Experience with Intravenous
Administration
The data
described below reflect exposure to Benlysta administered intravenously plus
standard therapy compared with placebo plus standard therapy in 2,133 patients
in 3 controlled trials. Patients received Benlysta plus standard therapy at
doses of 1 mg/kg (n = 673), 4 mg/kg (n = 111; Trial 1
only), or 10 mg/kg (n = 674), or placebo plus standard therapy
(n = 675) intravenously over a 1-hour period on Days 0, 14, 28, and
then every 28 days. In 2 of the trials (Trial 1 and Trial 3), treatment was
given for 48 weeks, while in the other trial (Trial 2) treatment was given for
72 weeks [see Clinical Studies (14.1)]. Because there was no apparent dose-related increase in the
majority of adverse events observed with Benlysta, the safety data summarized
below are presented for the 3 intravenous doses pooled, unless otherwise
indicated; the adverse reaction table displays the results for the recommended
intravenous dose of 10 mg/kg compared with placebo.
The
population had a mean age of 39 years (range: 18 to 75), 94% were female, and
52% were white. In these trials, 93% of patients treated with Benlysta plus
standard therapy reported an adverse event compared with 92% treated with
placebo plus standard therapy.
The most
common serious adverse events were serious infections (6.0% and 5.2% in the groups
receiving Benlysta and placebo plus standard therapy, respectively), some of
which were fatal [see Warnings and Precautions (5.2)].
The most
commonly reported adverse events, occurring in ≥5% of patients in clinical
trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia,
pain in extremity, depression, migraine, and pharyngitis.
The
proportion of patients who discontinued treatment due to any adverse reaction
during the controlled clinical trials was 6.2% for patients receiving Benlysta
plus standard therapy and 7.1% for patients receiving placebo plus standard
therapy. The most common adverse reactions resulting in discontinuation of
treatment (≥1% of patients receiving Benlysta or placebo) were infusion
reactions (1.6% Benlysta and 0.9% placebo), lupus nephritis (0.7% Benlysta and
1.2% placebo), and infections (0.7% Benlysta and 1.0% placebo).
Table 1 lists
adverse reactions, regardless of causality, occurring in at least 3% of
patients with SLE who received Benlysta 10 mg/kg plus standard therapy and at
an incidence at least 1% greater than that observed with placebo plus standard
therapy in the 3 controlled studies.
Table 1. Incidence of Adverse Reactions
Occurring in at Least 3% of Patients Treated with Benlysta 10 mg/kg plus
Standard Therapy and at Least 1% More Frequently than in Patients Receiving
Placebo plus Standard Therapy
|
|
Preferred Term
|
Benlysta
10 mg/kg +
Standard Therapy
(n = 674)
%
|
Placebo +
Standard Therapy
(n = 675)
%
|
|
Nausea
|
15
|
12
|
|
Diarrhea
|
12
|
9
|
|
Pyrexia
|
10
|
8
|
|
Nasopharyngitis
|
9
|
7
|
|
Bronchitis
|
9
|
5
|
|
Insomnia
|
7
|
5
|
|
Pain in extremity
|
6
|
4
|
|
Depression
|
5
|
4
|
|
Migraine
|
5
|
4
|
|
Pharyngitis
|
5
|
3
|
|
Cystitis
|
4
|
3
|
|
Leukopenia
|
4
|
2
|
|
Gastroenteritis viral
|
3
|
1
|
Clinical Trials Experience with Subcutaneous
Administration
The data
described below reflect exposure to Benlysta administered subcutaneously plus
standard therapy compared with placebo plus standard therapy in
836 patients in a controlled trial (Trial 4). In addition to standard
therapy, patients received Benlysta 200 mg (n = 556) or placebo
(n = 280) (2:1 randomization) once weekly for up to
52 weeks [see Clinical Studies (14.2)].
The
overall population had a mean age of 39 years (range: 18 to 77), 94% were
female, and 60% were white. In the trial, 81% of patients treated with Benlysta
plus standard therapy reported an adverse event compared with 84% treated with
placebo plus standard therapy. The proportion of patients who discontinued
treatment due to any adverse reaction during the controlled clinical trial was
7.2% of patients receiving Benlysta plus standard therapy and 8.9% of patients
receiving placebo plus standard therapy.
The
safety profile observed for Benlysta administered subcutaneously plus standard
therapy was consistent with the known safety profile of Benlysta administered
intravenously plus standard therapy, with the exception of local injection site
reactions
Injection Site Reactions
In the
clinical study for Benlysta administered subcutaneously, the frequency of
injection site reactions was 6.1% (34/556) for patients receiving Benlysta plus
standard therapy and 2.5% (7/280) for patients receiving placebo plus standard
therapy. These injection site reactions (most commonly pain, erythema,
hematoma, pruritus, and induration) were mild to moderate in severity. The
majority (94%) did not necessitate discontinuation of treatment.
Postmarketing Experience
The
following adverse reactions have been identified during postapproval use of
Benlysta. 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 [see Warnings and Precautions (5.3)].
Immunogenicity
As with all therapeutic proteins, there is 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 antibodies to belimumab with the incidence of
antibodies in other studies or to other products may be misleading.
In Trials 2 and 3 (intravenous dosing), anti-belimumab
antibodies were detected in 4 of 563 (0.7%) patients receiving Benlysta
10 mg/kg and in 27 of 559 (4.8%) patients receiving Benlysta 1 mg/kg.
The reported frequency for the group receiving 10 mg/kg may underestimate
the actual frequency due to lower assay sensitivity in the presence of high
drug concentrations. Neutralizing antibodies were detected in 3 patients
receiving Benlysta 1 mg/kg. Three patients with anti-belimumab antibodies
experienced mild infusion reactions of nausea, erythematous rash, pruritus,
eyelid edema, headache, and dyspnea; none of the reactions was
life-threatening. In Trial 4 (subcutaneous dosing), there was no formation of
anti-belimumab antibodies in 556 patients receiving Benlysta 200 mg during
the 52-week placebo-controlled period. The clinical relevance of the presence
of anti-belimumab antibodies is not known.
The data reflect the percentage of patients whose test results
were positive for antibodies to belimumab in specific assays.
Drug Interactions
Formal drug interaction studies have not been performed with
Benlysta. In clinical trials of patients with SLE, Benlysta was administered
concomitantly with other drugs, including corticosteroids, antimalarials,
immunomodulatory, and immunosuppressive agents (including azathioprine,
methotrexate, and mycophenolate), angiotensin pathway antihypertensives,
HMG-CoA reductase inhibitors (statins), and 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)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy
outcomes in women exposed to Benlysta during pregnancy. Healthcare
professionals are encouraged to register patients by calling 1-877-681-6296.
Risk Summary
Limited data on use of Benlysta in pregnant women, from
observational studies, published case reports, and postmarketing surveillance,
are insufficient to determine whether there is a drug-associated risk for major
birth defects or miscarriage. There are risks to the mother and fetus
associated with SLE [see Clinical Considerations].
Monoclonal antibodies, such as belimumab, are actively transported across the
placenta during the third trimester of pregnancy and may affect immune response
in the in utero-exposed infant [see Clinical
Considerations]. In an animal combined embryo-fetal and pre-
and post-natal development study with monkeys that received belimumab by
intravenous administration, there was no evidence of embryotoxicity or fetal
malformations with exposures approximately 9 times (based on intravenous
administration) and 20 times (based on subcutaneous administration) the
exposure at the maximum recommended human dose (MRHD). Belimumab-related
findings in monkey fetuses and/or infants included reductions of B-cell counts,
reductions in the density of lymphoid tissue B-lymphocytes in the spleen and
lymph nodes, and altered IgG and IgM titers. The no-adverse-effect-level
(NOAEL) was not identified for these findings; however, they were reversible
within 3 to 12 months after the drug was discontinued [see
Data]. Based on animal data and the mechanism of action of
belimumab, the immune system in infants of treated mothers may be adversely
affected. It is unknown, based on available data, whether immune effects, if
identified, are reversible [see Clinical Pharmacology (12.1)].
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In theU.S.general
population, the background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with SLE are at increased risk
of adverse pregnancy outcomes, including worsening of the underlying disease,
premature birth, spontaneous abortion, and intrauterine growth restriction.
Maternal lupus nephritis increases the risk of hypertension and preeclampsia/eclampsia.
Passage of maternal anti-phospholipid antibodies across the placenta may result
in adverse neonatal outcomes, including neonatal lupus and congenital heart
block.
Fetal/Neonatal Adverse Reactions: Monoclonal antibodies are increasingly transported
across the placenta as pregnancy progresses, with the largest amount
transferred during the third trimester. Risks and benefits should be considered
prior to administering live or live-attenuated vaccines to infants exposed to
Benlysta in utero. Monitor an infant of a treated mother for B-cell reduction
and other immune dysfunction [see Warnings
and Precautions (5.7)].
Data
Animal Data: In
a combined embryo-fetal and pre- and post-natal development study, pregnant
cynomolgus monkeys received belimumab at intravenous doses of 0, 5, or
150 mg/kg every 2 weeks from confirmation of pregnancy at Gestation Days
(GD) 20 to 22, throughout the period of organogenesis (up to approximately GD
50), and continuing to either the day of scheduled cesarean section
(GD 150 [late third trimester]) or the day of parturition. There was no
evidence of maternal toxicity, embryotoxicity, or teratogenicity at exposure approximately
9 times the MRHD of 10 mg/kg intravenously or 20 times the MRHD
of 200 mg subcutaneously (on an AUC basis with maternal animal intravenous
doses up to 150 mg/kg). Belimumab-related findings in mothers included
reductions of immature and mature B-cell counts and in fetuses and/or infants
included reductions of immature and mature B-cell counts, reductions in the
density of lymphoid tissue B-lymphocytes in the spleen and lymph nodes, reduced
spleen weights, increased IgG titers, and reduced IgM titers. B-cell counts in
infant monkeys exposed to belimumab in utero recovered by 3 months of age
and in mothers after 1 year. IgG and IgM levels in infant monkeys
recovered by 6 months of age and the reductions in B-lymphocytes in the
lymph nodes and spleen were reversed by 1 year of age. Belimumab crossed
the placenta, as it was detected in fetal cord blood and amniotic fluid on
GD 150.
Lactation
Risk Summary
No
information is available on the presence of belimumab in human milk, the
effects of the drug on the breastfed infant, or the effects of the drug on milk
production. Belimumab was detected in the milk of cynomolgus monkeys; however,
due to species-specific differences in lactation physiology, animal data may not
predict drug levels in human milk. Maternal IgG is known to be present in human
milk. If belimumab is transferred into human milk, the effects of local
exposure in the gastrointestinal tract and potential limited systemic exposure
in the infant to belimumab are unknown. The lack of clinical data during
lactation precludes clear determination of the risk of Benlysta to an infant
during lactation; therefore, the developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for
Benlysta, and any potential adverse effects on the breastfed child from
Benlysta or from the underlying maternal condition.
Females and Males of Reproductive Potential
Contraception
Following
an assessment of benefit versus risk, if prevention of pregnancy is warranted,
females of reproductive potential should use effective contraception during
treatment and for at least 4 months after the final treatment.
Pediatric Use
Safety
and effectiveness of Benlysta have not been established in children.
Geriatric Use
Clinical
studies of Benlysta did not include sufficient numbers of subjects aged 65 or
older to determine whether they respond differently from younger subjects. Use
with caution in elderly patients.
Renal Impairment
The
safety and efficacy of Benlysta were evaluated in studies that included
patients with SLE who had mild (creatinine clearance [CrCl] ≥60 and
<90 mL/min), moderate (CrCl ≥30 and <60 mL/min), or severe
(CrCl ≥15 and <30 mL/min) renal impairment. No dosage adjustment is recommended
in patients with renal impairment.
Hepatic Impairment
No formal
trials were conducted to examine the effects of hepatic impairment on the
pharmacokinetics of belimumab. No dosage adjustment is recommended in patients
with hepatic impairment.
Racial Groups
In Trial
2 and Trial 3 (intravenous dosing), SLE Responder Index-4 (SRI-4) response
rates were lower for black patients receiving Benlysta plus standard therapy
relative to black patients receiving placebo plus standard therapy [see
Clinical Studies (14.1)]. In Trial 4 (subcutaneous
dosing), SRI-4 response was slightly higher for black patients receiving
Benlysta plus standard therapy relative to black patients receiving placebo
plus standard therapy, but the treatment difference was not as large as that
observed in the overall population and no definitive conclusion can be drawn
from this subgroup analysis [see Clinical Studies (14.2)].
Caution should be used when considering treatment with Benlysta in
black/African-American patients
Overdosage
There is
limited experience with overdosage of belimumab. Adverse reactions reported in
association with cases of overdose have been consistent with those expected for
belimumab.
Two doses
of up to 20 mg/kg have been given intravenously to humans with no increase in
incidence or severity of adverse reactions compared with doses of 1, 4, or 10
mg/kg.
Benlysta Description
Belimumab
is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte
stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of
approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a
murine cell (NS0) expression system.
Intravenous Infusion
Benlysta
(belimumab) for injection is a sterile, white to off-white, preservative‑free,
lyophilized powder in a single-dose vial for reconstitution and dilution prior
to intravenous infusion. Benlysta for injection is supplied as 120 mg per vial
and 400 mg per vial and requires reconstitution with Sterile Water for Injection,
USP (1.5 mL and 4.8 mL, respectively) to obtain a concentration of
80 mg/mL [see Dosage and Administration (2.1)]. After reconstitution, each vial allows for withdrawal of
1.5 mL (120 mg) or 5 mL (400 mg). Each mL delivers 80 mg belimumab,
citric acid (0.16 mg), polysorbate 80 (0.4 mg), sodium citrate
(2.7 mg), and sucrose (80 mg), with a pH of 6.5.
The vial
stoppers are not made with natural rubber latex.
Subcutaneous Injection
Benlysta
(belimumab) injection is a sterile, preservative-free, clear to opalescent, and
colorless to pale yellow solution for subcutaneous use. It is supplied in a
1-mL single-dose prefilled autoinjector with a fixed 27-gauge, half-inch needle
or in a 1-mL single-dose prefilled syringe with a fixed 27-gauge, half-inch
needle with a needle guard. Each 1 mL delivers 200 mg belimumab,
L-arginine hydrochloride (5.3 mg), L-histidine (0.65 mg), L-histidine
monohydrochloride (1.2 mg), polysorbate 80 (0.1 mg), and sodium
chloride (6.7 mg), with a pH of 6.0.
The
autoinjectors and prefilled syringes are not made with natural rubber latex.
Benlysta - Clinical Pharmacology
Mechanism of Action
Benlysta
is a BLyS-specific inhibitor that blocks the binding of soluble BLyS, a B-cell
survival factor, to its receptors on B cells. Benlysta does not bind B
cells directly, but by binding BLyS, Benlysta inhibits the survival of B cells,
including autoreactive B cells, and reduces the differentiation of B cells into
immunoglobulin-producing plasma cells.
Pharmacodynamics
Treatment
with Benlysta significantly reduced circulating CD19+, CD20+, naïve, and
activated B cells, and the SLE B‑cell subset at Week 52. Reductions
in naïve and the SLE B‑cell subset were observed as early as Week 8 and
sustained to Week 52. Memory cells increased initially and slowly declined
toward baseline levels by Week 52. The clinical relevance of these effects
on B cells has not been established.
Treatment
with Benlysta led to reductions in IgG and anti-double-stranded DNA antibodies
(anti-dsDNA) which were observed as early as Week 8 and sustained through
Week 52. In patients with low complement levels at baseline, treatment led
to increases in complement C3 and C4 as early as Week 12 and were
sustained through Week 52. The clinical relevance of normalizing these
biomarkers has not been definitively established.
Pharmacokinetics
Intravenous Infusion
The
pharmacokinetic parameters displayed in Table 2 are based on population
parameter estimates from 563 patients who received Benlysta 10 mg/kg.
Table 2. Population Pharmacokinetic
Parameters in Patients with SLE after Intravenous Infusion of Benlysta 10
mg/kga
|
|
a Intravenous
infusions were administered at 2-week intervals for the first 3 doses
and at 4-week intervals thereafter.
|
|
Pharmacokinetic
Parameter
|
Population Estimates
(n =
563)
|
|
Peak concentration (Cmax, mcg/mL)
|
313
|
|
Area under the curve (AUC0-∞, day●mcg/mL)
|
3,083
|
|
Distribution half-life (t½, days)
|
1.8
|
|
Terminal half-life (t½, days)
|
19.4
|
|
Systemic clearance (CL, mL/day)
|
215
|
|
Volume of distribution (Vss, L)
|
5
|
Subcutaneous Injection
The
pharmacokinetic parameters displayed in Table 3 are based on population
parameter estimates from 661 subjects after subcutaneous administration of
belimumab. The time to reach maximum serum concentration (Cmax) was 2.6 days (tmax)
after administration at steady state. The bioavailability of belimumab was
approximately 74%. With weekly subcutaneous administration there were minor
fluctuations around the average concentration (Cavg 104 mcg/mL),
with Cmin (97 mcg/mL) being only slightly below Cavg.
Table 3. Population Pharmacokinetic
Parameters after Subcutaneous Administration of Benlysta
|
|
Pharmacokinetic
Parameter
|
Population Estimates
(n =
661)
|
|
Peak concentration (Cmax, mcg/mL)
|
108
|
|
Area under the curve (AUC0-∞, day●mcg/mL)
|
726
|
|
Distribution half-life (t½, days)
|
1.1
|
|
Terminal half-life (t½, days)
|
18.3
|
|
Systemic clearance (CL, mL/day)
|
204
|
|
Volume of distribution (Vss, L)
|
5
|
Specific Populations
The
following information is based on the population pharmacokinetic analyses of
intravenous administration and subcutaneous administration of Benlysta.
Age: Age
did not significantly influence the pharmacokinetics of belimumab, where the
majority of subjects were between 18 and 45 years (70% with intravenous
dosing; 74% with subcutaneous dosing). No pharmacokinetic data are available in
pediatric patients. Limited pharmacokinetic data are available for elderly
patients as less than 2% of the subjects included in the pharmacokinetic
analysis were 65 years or older [see Use in
Specific Populations (8.5)].
Male and Female Patients: Gender did not significantly influence belimumab
pharmacokinetics in the largely female trial population (94% with intravenous
dosing; 85% with subcutaneous dosing).
Racial Groups: Race did not significantly influence belimumab
pharmacokinetics. The racial distribution with intravenous administration was
53% white, 16% Asian, 16% Alaska native/American Indian, and 14% black. The
racial distribution with subcutaneous administration was 61% white, 20% Asian,
11% black, and 6% Alaska native/American Indian.
Weight: Body
weight and body mass index (BMI) had no clinically relevant effect on the
pharmacokinetics of belimumab administered subcutaneously. No dose adjustment
is recommended based on weight or BMI for subcutaneous administration.
Patients with Renal Impairment: No formal trials were conducted to examine the
effects of renal impairment on the pharmacokinetics of belimumab. Benlysta was
studied in a limited number of patients with SLE who had mild (CrCl ≥60 and
<90 mL/min), moderate (CrCl ≥30 and <60 mL/min), or severe
(CrCl ≥15 and <30 mL/min) renal impairment: 770 patients with mild
renal impairment, 261 patients with moderate renal impairment, and
14 patients with severe renal impairment received belimumab intravenously;
121 patients with mild renal impairment and 30 patients with moderate
renal impairment received belimumab subcutaneously. [See Use in
Specific Populations (8.6).]
Patients with Hepatic Impairment: No formal trials were conducted to examine the
effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline
ALT and AST levels did not significantly influence belimumab
pharmacokinetics. [See Use in Specific Populations (8.7).]
Drug Interaction Studies
No formal
drug interaction studies have been conducted with Benlysta. Concomitant use of
mycophenolate, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and
HMG-CoA reductase inhibitors did not significantly influence belimumab
pharmacokinetics. Coadministration of steroids and angiotensin-converting
enzyme (ACE) inhibitors resulted in an increase of systemic clearance of
belimumab that was not clinically significant because the magnitude was well
within the range of normal variability of clearance. The effect of belimumab on
the pharmacokinetics of other drugs has not been evaluated.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term
animal studies have not been performed to evaluate the carcinogenic potential
of belimumab.
Effects
on male and female fertility have not been directly evaluated in animal
studies.
Clinical Trials Experience with Intravenous
Administration
The
safety and effectiveness of Benlysta administered intravenously plus standard
therapy were evaluated in 3 randomized, double‑blind, placebo‑controlled trials
involving 2,133 patients with SLE according to the American College of
Rheumatology criteria (Trials 1, 2, and 3). Patients with severe active lupus
nephritis and severe active CNS lupus were excluded. Patients were on a stable
standard therapy SLE treatment regimen comprising any of the following (alone
or in combination): corticosteroids, antimalarials, NSAIDs, and
immunosuppressives. Use of other biologics and intravenous cyclophosphamide
were not permitted.
Trial 1: Benlysta 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1
enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg Benlysta plus
standard therapy compared with placebo plus standard therapy over 52 weeks in
patients with SLE. Patients had to have a Safety of Estrogens in Lupus
Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity
Index (SELENA-SLEDAI) score of >4
at baseline and a history of autoantibodies (anti-nuclear antibody [ANA] and/or
anti-double-stranded DNA [anti-dsDNA]), but 28% of the population was
autoantibody negative at baseline. The co-primary endpoints were percent change
in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No
significant differences between any of the groups receiving Benlysta and the
group receiving placebo were observed. Exploratory analysis of this trial
identified a subgroup of patients (72%) who were autoantibody positive in whom
Benlysta appeared to offer benefit. The results of this trial informed the
design of Trials 2 and 3 and led to the selection of a target population and
indication that is limited to autoantibody-positive SLE patients.
Trials 2 and 3: Benlysta 1 mg/kg and 10 mg/kg
Trials 2
and 3 were randomized, double‑blind, placebo‑controlled trials in patients with
SLE that were similar in design except duration - Trial 2
(N = 819) was 76 weeks’ duration and Trial 3 (N = 865)
was 52 weeks’ duration. Patients had active SLE disease with a SELENA‑SLEDAI
score ≥6 and positive autoantibody test results at screening. Patients were
excluded from the trial if they had ever received treatment with a B‑cell-targeted
agent or if they were currently receiving other biologic agents. Intravenous
cyclophosphamide was not permitted within the previous 6 months or during the
trial. Trial 2 was conducted primarily in North America and Europe.
Trial 3 was conducted in South America, Eastern Europe, Asia, and
Australia.
Baseline
concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%),
immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine,
methotrexate, and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3:
67%). Most patients (>70%) were receiving 2 or more classes of SLE
medications.
In Trial
2 and Trial 3, more than 50% of patients had 3 or more active organ systems
involved at baseline. The most common active organ systems at baseline based on
SELENA-SLEDAI were mucocutaneous (82% in both trials), immune (Trial 2: 74%,
Trial 3: 85%), and musculoskeletal (Trial 2: 73%, Trial 3: 59%). Less than 16%
of patients had some degree of renal activity and less than 7% of patients had
activity in the vascular, cardio-respiratory, or CNS systems.
At
screening, patients were stratified by disease severity based on their SELENA‑SLEDAI
score (≤9 vs. ≥10), proteinuria level
(<2 g/24 h vs. ≥2 g/24 h), and race (African
or Indigenous-American descent vs. other), and then randomly assigned to
receive Benlysta 1 mg/kg, Benlysta 10 mg/kg, or placebo in addition
to standard therapy. The patients were administered trial medication
intravenously over a 1‑hour period on Days 0, 14, 28, and then every
28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2.
The
primary efficacy endpoint was a composite endpoint (SLE Responder Index-4 or
SRI-4) that defined response as meeting each of the following criteria at
Week 52 compared with baseline:
•
≥4‑point
reduction in the SELENA‑SLEDAI score, and
•
no new
British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new
BILAG B organ domain scores, and
•
no
worsening (<0.30‑point increase) in Physician’s Global Assessment (PGA)
score.
The SRI uses the SELENA‑SLEDAI score as an objective measure of
reduction in global disease activity; the BILAG index to ensure no significant
worsening in any specific organ system; and the PGA to ensure that improvements
in disease activity are not accompanied by worsening of the patient’s condition
overall.
In both Trials 2 and 3, the proportion of patients with SLE
achieving an SRI-4 response, as defined for the primary endpoint, was
significantly higher in the group receiving Benlysta 10 mg/kg plus
standard therapy than in the group receiving placebo plus standard therapy. The
effect on the SRI-4 was not consistently significantly different for patients
receiving Benlysta 1 mg/kg plus standard therapy relative to placebo plus
standard therapy in both trials. The 1-mg/kg dose is not recommended. The
trends in comparisons between the treatment groups for the rates of response
for the individual components of the endpoint were generally consistent with
that of the SRI-4 (Table 4). At Week 76 in Trial 2, the SRI-4 response
rate with Benlysta 10 mg/kg was not significantly different from that of
placebo (39% and 32%, respectively).
Table 4. Clinical Response Rate in Patients with SLE after 52 Weeks
of Treatment
|
|
|
Trial 2
|
Trial 3
|
|
a Patients
dropping out of the trial early or experiencing certain increases in
background medication were considered as failures in these analyses. In both
trials, a higher proportion of placebo patients were considered as failures
for this reason compared with the groups receiving Benlysta.
b The
1-mg/kg dose is not recommended.
|
|
Response
|
Placebo +
Standard
Therapy
(n = 275)
|
Benlysta
1
mg/kg + Standard Therapyb
(n = 271)
|
Benlysta
10
mg/kg + Standard Therapy
(n = 273)
|
Placebo +
Standard
Therapy
(n = 287)
|
Benlysta
1
mg/kg + Standard Therapyb
(n = 288)
|
Benlysta
10
mg/kg + Standard Therapy
(n = 290)
|
|
SLE Responder Index-4 (SRI-4)a
|
34%
|
41%
(P = 0.104)
|
43%
(P = 0.021)
|
44%
|
51%
(P = 0.013)
|
58%
(P <0.001)
|
|
Odds Ratio
(95% CI) vs. placebo
|
|
1.3
(0.9, 1.9)
|
1.5
(1.1, 2.2)
|
|
1.6
(1.1, 2.2)
|
1.8
(1.3, 2.6)
|
|
Components of SLE Responder Index-4 (SRI-4)
|
|
Percent of patients with reduction in SELENA-SLEDAI ≥4
|
36%
|
43%
|
47%
|
46%
|
53%
|
58%
|
|
Percent of patients with no worsening by BILAG index
|
65%
|
75%
|
69%
|
73%
|
79%
|
81%
|
|
Percent of patients with no worsening by PGA
|
63%
|
73%
|
69%
|
69%
|
79%
|
80%
|
The
reduction in disease activity seen in the SRI-4 was related primarily to
improvement in the most commonly involved organ systems; namely, mucocutaneous,
musculoskeletal, and immune.
Effect in Black/African-American Patients
Exploratory
sub-group analyses of SRI-4 response rate in black patients (n = 148)
were performed. The SRI-4 response rate in black patients in groups receiving
Benlysta plus standard therapy was less than that in the group receiving
placebo plus standard therapy (22/50 or 44% for placebo, 15/48 or 31% for
Benlysta 1 mg/kg, and 18/50 or 36% for Benlysta 10 mg/kg). Although no
definitive conclusion can be drawn from this subgroup analysis, caution should
be used when considering treatment with Benlysta in black/African-American
patients.
Effect on Concomitant Steroid Treatment
In Trial
2 and Trial 3, 46% and 69% of patients, respectively, were receiving prednisone
at doses >7.5 mg/day at baseline. The proportion of patients able to reduce
their average prednisone dose by at least 25% to ≤7.5 mg/day during
Weeks 40 through 52 was not consistently significantly different for
Benlysta plus standard therapy relative to placebo plus standard therapy in
both trials. In Trial 2, 17% of patients receiving Benlysta 10 mg/kg plus
standard therapy and 19% of patients receiving Benlysta 1 mg/kg plus
standard therapy achieved this level of steroid reduction compared with 13% of
patients receiving placebo plus standard therapy. In Trial 3, 19%, 21%, and 12%
of patients receiving Benlysta 10 mg/kg, Benlysta 1 mg/kg, and
placebo, respectively, plus standard therapy achieved this level of steroid
reduction.
Effect on Severe SLE Flares
The
probability of experiencing a severe SLE flare, as defined by a modification of
the SELENA Trial flare criteria, which excluded severe flares triggered only by
an increase of the SELENA-SLEDAI score to >12, was calculated for both
Trials 2 and 3. The proportion of patients having at least 1 severe flare over
52 weeks was not consistently significantly different for Benlysta plus
standard therapy relative to placebo plus standard therapy in both trials. In
Trial 2, 18% of patients receiving Benlysta 10 mg/kg plus standard therapy
and 16% of patients receiving Benlysta 1 mg/kg plus standard therapy had a
severe flare compared with 24% of patients receiving placebo plus standard
therapy. In Trial 3, 14%, 18%, and 23% of patients receiving Benlysta
10 mg/kg, Benlysta 1 mg/kg and placebo, respectively, plus standard
therapy had a severe flare.
Clinical Trials Experience with Subcutaneous
Administration
The
safety and effectiveness of Benlysta administered subcutaneously were evaluated
in a randomized, double‑blind, placebo‑controlled trial involving
836 patients with SLE according to the American College of Rheumatology
criteria (Trial 4). Patients with severe active lupus nephritis and severe
active CNS lupus were excluded. The trial (2:1 randomization) evaluated
Benlysta 200 mg once weekly plus standard therapy (n = 556)
compared with placebo once weekly plus standard therapy (n = 280)
over 52 weeks in patients with active SLE disease. Patients had to have a
SELENA-SLEDAI score of ≥8 and positive autoantibody test (anti-nuclear antibody
[ANA] and/or anti-double-stranded DNA [anti-dsDNA] results at screening.
No
significant differences in baseline patient characteristics were observed
between treatment groups. In some countries, treatment with a B-cell-targeted
agent was permitted if received a year or more prior to baseline, otherwise,
treatment with a B-cell-targeted agent was not permitted. Patients were
excluded from the trial if they were currently receiving other biologic agents.
Anti-tumor necrosis factor therapy, intravenous cyclophosphamide, interleukin-1
receptor antagonist, intravenous immunoglobulin (IVIG), prednisone >100 mg/day,
and plasmapheresis were not permitted within the previous 3 months or
during the trial. The trial was conducted in North America, South America,
Europe, and Asia. Baseline concomitant medications included corticosteroids
(86%), antimalarials (69%), and immunosuppressives (46% including azathioprine,
methotrexate, and mycophenolate). Most patients (approximately 80%) were
receiving 2 or more classes of SLE medications.
More than
50% of patients had 3 or more active organ systems involved at baseline. The
most common active organ systems at baseline based on SELENA-SLEDAI were
mucocutaneous (88%), musculoskeletal (78%), and immunologic (76%). Overall, 12%
of patients had some degree of renal activity and less than 15% of patients had
activity in the vascular, cardio-respiratory, or CNS systems. Patients were
stratified by disease severity based on their SELENA-SLEDAI score (≤9 vs. ≥10),
complement level (C3 and/or C4 low vs. other), and race (black vs. other), and
then randomly assigned to receive Benlysta 200 mg plus standard therapy or
placebo once weekly plus standard therapy.
The
primary efficacy endpoint was the SLE Responder Index-4 (SRI-4) at Week 52
as described in the intravenous trials. Secondary efficacy endpoints included
time to first severe flare (as measured by the modified SELENA-SLEDAI SLE Flare
Index) and the proportion of patients receiving prednisone >7.5 mg/day
at baseline whose average prednisone dose had been reduced by ≥25% to ≤7.5 mg/day
during Weeks 40 through 52.
The
proportion of patients achieving an SRI-4 response was significantly higher in
patients receiving Benlysta plus standard therapy compared with placebo plus
standard therapy. The trends comparing the treatment groups with respect to the
probability of response for the individual components of the endpoint were
consistent with that of the SRI-4 (Table 5).
Table 5. Clinical Response Rate in
Patients with SLE after 52 Weeks of Treatment
|
|
a Patients dropping out of the trial early or experiencing certain
increases in background medication were considered as failures in these
analyses. A higher proportion of patients receiving placebo plus standard
therapy were considered as failures for this reason compared with the group
receiving Benlysta plus standard therapy.
|
|
Response
|
Placebo +
Standard
Therapy
(n = 279)
|
Benlysta +
Standard
Therapy
(n = 554)
|
|
SLE Responder Index-4(SRI-4)a
|
48%
|
61%
P = 0.0006
|
|
Odds Ratio
(95% CI) vs. placebo
|
|
1.7
(1.3, 2.3)
|
|
Components of SLE Responder Index-4 (SRI-4)
|
|
Percent of patients with reduction in SELENA-SLEDAI ≥4
|
49%
|
62%
|
|
Percent of patients with no worsening by BILAG index
|
74%
|
81%
|
|
Percent of patients with no worsening by PGA
|
73%
|
81%
|
The
reduction in disease activity seen in the SRI-4 was related primarily to
improvement in the most commonly involved organ systems, namely, mucocutaneous,
musculoskeletal, immunologic, and vascular.
The
proportion of SRI-4 responders by visit through Week 52 is shown in
Figure 1.
Figure 1. Proportion (%) of SRI-4 Responders (+/- Standard
Error) by Visita
a The same patients may not have responded at
each timepoint.
Effect in Black/African-American Patients
Exploratory
sub-group analyses of SRI-4 response rate in black patients (n = 91)
were performed. The SRI-4 response rate was slightly higher in black patients
receiving Benlysta plus standard therapy (26/58 or 45%) compared with the group
receiving placebo plus standard therapy (13/33 or 39%), but the treatment
difference was not as large as that observed in the overall population and no
definitive conclusion can be drawn from this subgroup analysis. Caution should
be used when considering treatment with Benlysta in black/African-American
patients.
Effect on Concomitant Steroid Treatment
At
baseline, 60% of patients were receiving prednisone at doses >7.5 mg/day.
Among these patients, 18% of patients receiving Benlysta plus standard therapy
reduced their average prednisone dose by at least 25% to ≤7.5 mg/day
during Weeks 40 through 52 compared with 12% of patients on placebo plus
standard therapy; this difference was not statistically significant
(OR = 1.65 [95% CI: 0.95, 2.84]).
Effect on Severe SLE Flares
The
probability of experiencing a severe SLE flare, as measured by the modified
SELENA-SLEDAI SLE Flare Index, excluding severe flares triggered only by an
increase of the SELENA-SLEDAI score to >12, was calculated. The proportion
of patients reporting at least 1 severe flare during the study was lower
in patients treated with Benlysta plus standard therapy (11%) compared with
those receiving placebo plus standard therapy (18%). Patients treated with
Benlysta plus standard therapy had a 49% lower risk of experiencing at least
1 severe flare during the 52 weeks of observation, relative to the
patients receiving placebo plus standard therapy (HR = 0.51
[95% CI: 0.35, 0.74]). Of the patients experiencing a severe flare, the
median time to the first severe flare was delayed in patients receiving
Benlysta plus standard therapy compared with placebo plus standard therapy
(171 days vs. 118 days).
How Supplied/Storage and Handling
Intravenous Infusion
Benlysta
(belimumab) for injection is a sterile, preservative-free, lyophilized powder
for reconstitution and dilution prior to intravenous infusion provided in
single-dose glass vials with a rubber stopper (not made with natural rubber
latex) and a flip-off seal. Each 5-mL vial contains 120 mg of belimumab. Each
20-mL vial contains 400 mg of belimumab.
Benlysta
vials are supplied as follows:
120 mg
belimumab in a 5-mL single-dose vial (NDC 49401-101-01)
400 mg
belimumab in a 20-mL single-dose vial (NDC 49401-102-01)
Refrigerate
vials at 2° to 8°C (36° to 46°F). Store vials in the original carton until use
to protect from light. Do not freeze. Avoid exposure to heat.
For Subcutaneous Injection
Benlysta
(belimumab) injection is a clear to opalescent, and colorless to pale yellow
solution for subcutaneous use. Each single-dose prefilled autoinjector or
single-dose prefilled syringe is designed to deliver 200 mg of belimumab
in 1 mL of solution and is supplied as follows:
200 mg/mL
single-dose prefilled autoinjector with 27-gauge, half-inch needle attached
(NDC 49401-088-01) in a carton of 4 (NDC 49401-088-35).
200 mg/mL
single-dose prefilled glass syringe with 27-gauge, half-inch needle attached
(NDC 49401-088-42) in a carton of 4 (NDC 49401-088-47).
Refrigerate
prefilled autoinjectors and prefilled syringes at 2°C to 8°C (36°F to 46°F).
Keep the product in the original carton to protect from light until the time of
use. Do not freeze. Do not shake. Avoid exposure to heat.
Benlysta
may be stored outside of the refrigerator up to 86°F (30°C) for up to
12 hours in the original container. Do not use and do not place back in
refrigerator if left out for more than 12 hours.
Patient Counseling Information
Advise
the patient to read the FDA-approved patient labeling (Medication Guide and
Instructions for Use). It is important that the patient’s overall health be
assessed at each visit and any questions resulting from the patient’s reading
of the Medication Guide and Instructions for Use be discussed.
For
patients receiving Benlysta, give patients the Medication Guide for Benlysta.
Mortality
Advise
patients that more patients receiving Benlysta in the main clinical trials died
than did patients receiving placebo treatment [see Warnings
and Precautions (5.1)].
Serious Infections
Advise
patients that Benlysta may decrease their ability to fight infections. Ask
patients if they have a history of chronic infections and if they are currently
on any therapy for an infection [see Warnings
and Precautions (5.2)]. Instruct patients to tell their healthcare provider if they
develop signs or symptoms of an infection.
Progressive Multifocal Leukoencephalopathy
Advise
patients to contact their healthcare professional if they experience new or
worsening neurological symptoms such as memory loss, confusion, dizziness or
loss of balance, difficulty talking or walking, or vision problems [see
Warnings and Precautions (5.2)].
Hypersensitivity Reactions/Anaphylaxis and Infusion Reactions
Educate
patients on the signs and symptoms of hypersensitivity reactions and infusion
reactions, including wheezing, difficulty breathing, angioedema, rash,
hypotension, bradycardia, and headache. Instruct patients to immediately tell
their healthcare provider if they experience symptoms of an allergic reaction
during or after the administration of Benlysta. Inform patients to tell their
healthcare provider about possible delayed reactions that may include a
combination of symptoms such as rash, nausea, fatigue, muscle aches, headache,
and/or facial swelling that may occur after administration of Benlysta [see
Warnings and Precautions (5.3, 5.4)].
Depression
Instruct
patients to contact their healthcare provider if they experience new or
worsening depression, suicidal thoughts, or other mood changes [see
Warnings and Precautions (5.5)].
Immunizations
Inform
patients that they should not receive live vaccines while taking Benlysta. Response
to vaccinations could be impaired by Benlysta [see Warnings
and Precautions (5.7)].
Pregnancy Registry
Inform
patients that there is a pregnancy registry to monitor fetal outcomes of
pregnant women exposed to Benlysta [see Use in
Specific Populations (8.1)].
Pregnancy
Inform
female patients of reproductive potential that Benlysta may impact the immune
system in infants of treated mothers and to inform their prescriber of a known
or suspected pregnancy [see Use in Specific Populations (8.1)].
Trademarks
are owned by or licensed to the GSK group of companies.
Manufactured
by
Human Genome Sciences, Inc.
(a
subsidiary of GlaxoSmithKline)
Rockville,
Maryland 20850
U.S.
License No. 1820
Marketed
by
GlaxoSmithKline
Research
Triangle Park, NC 27709
©2017 GSK
group of companies or its licensor.
BNL:8PI
DETACH
HERE AND GIVE MEDICATION GUIDE TO PATIENT.
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MEDICATION GUIDE
|
|
Benlysta (ben-LIST-ah)
(belimumab)
for injection, for
intravenous use
|
Benlysta (ben-LIST-ah)
(belimumab)
injection, for
subcutaneous use
|
|
What is the most
important information I should know about Benlysta?
Benlysta can cause serious side
effects. Some of these side effects may cause death. It is not known if
Benlysta causes these serious side effects. Tell your healthcare provider
right away if you have any of the symptoms listed below while receiving
Benlysta.
1.
Infections. Symptoms
of an infection can include:
• fever • urinating
often
• chills • coughing
up mucus
• pain
or burning with
urination • warm,
red, or painful skin or sores on your body
2.
Heart Problems. Symptoms of heart problems can include:
• chest
discomfort or
pain • nausea
• shortness
of
breath • dizziness
• cold
sweats
• discomfort
in other areas of the upper body
3.
Allergic (hypersensitivity) reactions. Serious allergic reactions can
happen on the day of, or in the days after, receiving Benlysta and may cause
death. Your healthcare provider will watch you closely while you are
receiving Benlysta given intravenously (infusion) and after your infusion for
signs of a reaction. Allergic reactions can sometimes be delayed. Tell your
healthcare provider right away if you have any of the following symptoms of
an allergic reaction following use of Benlysta:
• itching • dizziness
or fainting
• swelling
of the face, lips, mouth,
tongue, or
throat • headache
• trouble
breathing • nausea
• anxiousness • skin
rash
• low
blood pressure
• thoughts
of suicide or
dying • new
or worse depression
• attempt
to commit suicide • acting
on dangerous impulses
• trouble
sleeping (insomnia)
• other
unusual changes in
your
behavior or mood
• new
or worse
anxiety • thoughts
of hurting yourself
or
others
|
|
What is Benlysta?
Benlysta is a prescription
medicine used to treat adults with active systemic lupus erythematosus (SLE
or lupus) who are receiving other lupus medicines.
Benlysta contains belimumab
which is in a group of medicines called monoclonal antibodies. Lupus is a
disease of the immune system (the body system that fights infection). When
given together with other medicines for lupus, Benlysta decreases lupus
disease activity more than other lupus medicines alone.
•
It is not known
if Benlysta is safe and effective in people with severe active lupus
nephritis or severe active central nervous system lupus.
•
It is not known if Benlysta is safe and effective in
children.
|
|
Do not use Benlysta
if you:
•
are allergic to belimumab or any of the ingredients
in Benlysta. See the end of this Medication Guide for a complete list of
ingredients in Benlysta.
|
|
Before you receive
Benlysta, tell your healthcare provider about all of your medical conditions,
including if you:
•
think you have
an infection or have infections that keep coming back. You should not receive
Benlysta if you have an infection unless your healthcare provider tells you
to. See
“What is the most important information I should know about Benlysta?”
•
have or have
had mental health problems such as depression or thoughts of suicide.
•
have recently
received a vaccination or if you think you may need a vaccination. If you are
receiving Benlysta, you should not receive live vaccines.
•
are allergic to
other medicines.
•
are receiving
other biologic medicines, monoclonal antibodies or IV infusions of
cyclophosphamide (CYTOXAN).
•
have or have
had any type of cancer.
•
are pregnant or
plan to become pregnant. It is not known if Benlysta will harm your unborn
baby. Females who are able to become pregnant should talk to their healthcare
provider about whether or not they will use birth control (contraception) and
receive Benlysta. If Benlysta is recommended, you should use an effective
method of birth control while receiving Benlysta and for at least 4 months
after the final dose of Benlysta. Tell your healthcare provider right away if
you become pregnant during your treatment with Benlysta or if you think you
may be pregnant.
o
If you become
pregnant while receiving Benlysta, talk to your healthcare provider about enrolling
in the Benlysta Pregnancy Registry. You can enroll in this registry by
calling 1-877-681-6296. The purpose of this registry is to monitor the health
of you and your baby.
•
are
breastfeeding or plan to breastfeed. It is not known if Benlysta passes into
your breast milk. You and your healthcare provider should talk about whether
or not you should receive Benlysta and breastfeed.
Tell your healthcare provider
about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Know
the medicines you take. Keep a list of your medicines with you to show to
your healthcare provider and pharmacist when you get a new medicine.
|
|
How will I receive
Benlysta?
When administered intravenously (by vein)
•
You will be
given Benlysta by a healthcare provider through a needle placed in a vein (IV
infusion). It takes about 1 hour to give you the full dose of Benlysta.
•
Your healthcare
provider will tell you how often you should receive Benlysta.
•
Your healthcare
provider may give you medicines before you receive Benlysta to help reduce
your chance of having a reaction. A healthcare provider will watch you
closely while you are receiving Benlysta and after your infusion for signs of
a reaction. A healthcare provider will review the signs and symptoms of
possible allergic reactions that could happen after your infusion.
When administered
subcutaneously (under your skin)
•
Use Benlysta
exactly as your healthcare provider tells you to.
•
Read the Instructions for
Use that
comes with Benlysta for instructions about the right way to give your
injections at home.
•
Benlysta may be
prescribed as a single-dose autoinjector or as a single-dose prefilled
syringe.
•
Before you use
Benlysta, your healthcare provider will show you or your caregiver how to
give the injections and review the signs and symptoms of possible allergic
reactions.
•
Benlysta is
injected under your skin (subcutaneously) of your stomach (abdomen) or thigh.
•
Use Benlysta 1
time a week on the same day each week.
•
If you miss your dose of Benlysta on your planned
day, inject a dose as soon as you remember. Then, inject your next dose at
your regularly scheduled time or continue weekly dosing based on the new day
injected. In case you are not sure when to inject Benlysta, call your
healthcare provider. Do not use 2 doses on the same day to make up for a
missed dose.
|
|
What are the
possible side effects of Benlysta?
Benlysta can cause serious side effects, including:
See “What is the most important
information I should know about Benlysta?”
•
Progressive multifocal leukoencephalopathy (PML). PML is a serious and
life-threatening brain infection. Your chance of getting PML may be higher if
you are treated with medicines that weaken your immune system, including
Benlysta. PML can result in death or severe disability. If you notice any new
or worsening medical problems such as those below, tell your healthcare
provider right away:
○ memory
loss ○
difficulty talking or walking
○ trouble
thinking ○
loss of vision
○ dizziness or loss of balance
•
Cancer. Benlysta
may reduce the activity of your immune system. Medicines that affect the
immune system may increase your risk of certain cancers.
The most common side effects
of Benlysta include:
○
nausea ○
leg or arm pain
○
diarrhea ○
depression
○
fever ○
headache (migraine)
○ stuffy or runny nose
and ○
headache (migraine)
sore throat (nasopharyngitis) ○ pain,
redness, itching, or swelling at the site of injection (when given
subcutaneously)
○ persistent cough (bronchitis)
○ trouble sleeping (insomnia)
These
are not all the possible side effects of Benlysta. Call your doctor for
medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.
|
|
How should I store
Benlysta?
•
Store
autoinjectors and prefilled syringes in the refrigerator at 36°F to 46°F (2°C
to 8°C). Do not freeze.
•
Keep Benlysta
autoinjectors and prefilled syringes in the original package until time of
use to protect from light.
•
Do not shake.
Keep away from heat.
•
Do not use and
do not place back in the refrigerator if left out at room temperature for
more than 12 hours.
•
Safely throw
away medicine that is out of date or no longer needed.
Keep Benlysta and all
medicines out of the reach of children.
|
|
General information
about the safe and effective use of Benlysta.
Medicines are sometimes
prescribed for purposes other than those listed in a Medication Guide. Do not
use Benlysta for a condition for which it was not prescribed. Do not give
Benlysta to other people, even if they have the same symptoms that you have.
It may harm them.
This Medication Guide summarizes
the most important information about Benlysta. You can ask your healthcare
provider or pharmacist for information about Benlysta that is written for
healthcare professionals.
|
|
What are the
ingredients in Benlysta?
Active ingredient: belimumab.
Inactive ingredients (intravenous): citric acid, polysorbate 80, sodium citrate,
sucrose.
Inactive Ingredients (subcutaneous): L-arginine hydrochloride, L-histidine,
L-histidine monohydrochloride, polysorbate 80, sodium chloride.
|
|
For more information, go to www.Benlysta.com or call
1-877-423-6597
Benlysta is a registered
trademark owned by or licensed to the GSK group of companies. The other brand
listed is a trademark owned by or licensed to its respective owner and is not
owned by or licensed to the GSK group of companies. The maker of this brand
is not affiliated with and does not endorse the GSK group of companies or its
products.
Manufactured by
Human Genome Sciences, Inc.
(a subsidiary of
GlaxoSmithKline)
Rockville, Maryland 20850
U.S. License No. 1820
Marketed by
GlaxoSmithKline
Research Triangle Park, NC 27709
©2017 GSK group of companies or
its licensor.
BNL:7MG
|
This
Medication Guide has been approved by the U.S. Food and Drug
Administration. Revised:
07/2017
Instructions for Use
Benlysta (ben-LIST-ah)
(belimumab)
injection, for subcutaneous use
Prefilled Autoinjector
Read this Instructions for Use before you start to
use Benlysta and each time you refill your prescription. There may be new
information. You should also receive training from your healthcare provider on
how to use the autoinjector the right way. If you do not follow these
instructions the autoinjector may not work properly. Benlysta is for use under
the skin only (subcutaneous).
Important Storage Information
•
Keep refrigerated until 30 minutes
before use.
•
Keep in the original package until
time of use to protect from light.
•
Do
not freeze
Benlysta. Keep away from heat.
•
Do
not use
and do not place back in the refrigerator if Benlysta is
left out for more than 12 hours.
•
Keep out of the reach of children.
Important
Warnings
•
The autoinjector should be used only
1 time and then thrown away. See below, “Dispose of used autoinjector and
inspect.”
•
Do
not share
your Benlysta Autoinjector with other people. You may give other people a
serious infection, or get a serious infection from them.
•
Do
not shake
the autoinjector.
•
Do
not use
if dropped onto a hard surface.
•
Do
not remove
the Ring Cap until right before the injection.
Benlysta
Autoinjector Parts
Supplies
needed for the injection
Benlysta
Autoinjector
Alcohol
Swab (not
included)
Gauze
Pad or Cotton Ball (not included)
Sharps
Container (not
included)
1
Gather and check supplies
Gather
supplies
•
Remove 1 sealed tray containing an
autoinjector from the refrigerator.
•
Find a comfortable, well-lit, and
clean surface and place the following supplies within reach:
Benlysta Autoinjector
Alcohol Swab (not included)
Gauze Pad or Cotton Ball (not
included)
Sharps Container (not included)
Do
not perform
the injection if you do not have all the supplies listed.
Check
expiration date
Peel back the film of the tray and
remove the autoinjector.
Check the expiration date on the
autoinjector. See Figure A
•
Do
not use
if the expiration date has passed.
2
Prepare and inspect the Benlysta Autoinjector
Allow
to come to room temperature
•
Allow the autoinjector to sit at room
temperature for 30 minutes. See Figure B.
Do
not warm
the autoinjector in any other way. For example, do not warm in a microwave
oven, hot water, or in direct sunlight.
Do
not remove
the Ring Cap during this step
Inspect Benlysta solution
•
Look in the Inspection Window to
check that the Benlysta solution is colorless to slightly yellow in color. See
Figure C.
•
It is normal to see 1 or more air
bubbles in the solution.
•
Do
not use
if the solution looks cloudy, discolored, or has particles
3 Choose and clean the injection site
Choose the injection site
•
Choose where to inject (abdomen or
thigh). See Figure D.
•
Avoid injecting into the same site
each time or in areas where the skin is tender, bruised, red, or hard.
Do
not inject
within 2 inches of the belly button.
Clean
the injection site
•
Wash your hands.
•
Clean the injection site by wiping it
with an Alcohol Swab. Allow the skin to air dry. See Figure E.
.
•
Do
not touch
this area again before giving the injection.
4
Prepare for the injection
Remove
the Ring Cap
•
Do
not remove
the Ring Cap until right before you give the injection.
•
Remove the Ring Cap by pulling or
twisting it off. The Ring Cap may be twisted off in either a clockwise or
counter-clockwise direction. See Figure F.
•
Do
not put
the Ring Cap back onto the autoinjector
Position the autoinjector
•
Hold the autoinjector comfortably so
that you can see the Inspection Window. It is important that you can look at
the Inspection Window while giving the injection. You will look at the
Inspection Window to:
o
see that the purple indicator is
moving while you are injecting.
o
see that the purple indicator has
stopped to make sure that the dose is complete. See Figure G.
Position the autoinjector
straight over the injection site at a 90 degree angle. Make sure the Gold
Needle Guard is flat on the skin.
5
Inject Benlysta
Start
the injection
•
Firmly press the autoinjector all the
way down onto the injection site and hold in place. See Figure H.
•
This will insert the needle and start
the injection.
•
You may hear a “first click” at the
start of the injection and see the Purple Indicator start to move through the
Inspection Window. See Figure I.
Complete
the injection
•
Continue
to hold the autoinjector down until you see that the Purple Indicator has
stopped moving.
You may hear a "second
click" a few seconds before the Purple Indicator stops moving. See Figure
J.
•
The injection may take up to 15
seconds to complete.
•
When the injection is complete, lift
the autoinjector from the injection site
6 Dispose of used autoinjector and inspect
Dispose of the used autoinjector
Throw away (dispose of) the
used autoinjector and Ring Cap in a Sharps Container. See Figure K.
•
Put your used autoinjector in an
FDA-cleared sharps disposal container right away after use. Do not throw away
(dispose of) in your household trash.
•
If you do not have a FDA-cleared
sharps disposal container, you may use a household container that:
o
is made of a heavy-duty plastic,
o
can be closed with a tight-fitting,
puncture-resistant lid, without sharps being able to come out,
o
is upright and stable during use,
o
is leak-resistant, and
o
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 safe sharps disposal, and for specific information about
sharps disposal in the state that you live in, go to: http://www.fda.gov/safesharpsdisposal.
•
Do
not dispose
of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal
container.
Inspect
the injection site
•
There may be a small amount of blood
at the injection site. If needed, press a Cotton Ball or Gauze Pad on the
injection site.
•
Do
not rub
the injection site.
Additional
information
For more information about Benlysta,
go to www.Benlysta.com or call 1-877-423-6597.
This Instructions for Use has been
approved by the U.S. Food and Drug Administration.
Trademark is owned by or licensed to
the GSK group of companies.
Manufactured by Human Genome
Sciences, Inc., (a subsidiary of GlaxoSmithKline), Rockville, MD 20850
U.S. License No. 1820
©2017 GSK group of companies or its
licensor.
BNL:1IFU-A
Approved July 2017
Instructions
for Use
Benlysta
(ben-LIST-ah)
(belimumab)
injection,
for subcutaneous use
Prefilled
Syringe
Read this Instructions for Use before
you start to use Benlysta and each time you refill your prescription. There may
be new information. You should also receive training from your healthcare
provider on how to use the prefilled syringe the right way. If you do not
follow these instructions the prefilled syringe may not work properly. Benlysta
is for use under the skin only (subcutaneous).
Important
Storage Information
•
Keep refrigerated until 30 minutes
before use.
•
Keep in the original package until
time of use to protect from light.
•
Do
not freeze
Benlysta.
•
Keep
away from heat.
•
Do
not use
and do not place back in the refrigerator if Benlysta is
left out for more than 12 hours.
•
Keep out of the reach of children.
Important
Warnings
•
The prefilled syringe should be used
only 1 time and then thrown away. See below, “Dispose of used prefilled syringe
and inspect.”
o
Do
not share
your Benlysta prefilled syringe with other people. You may give other people a
serious infection, or get a serious infection from them.
o
Do
not shake
the prefilled syringe.
o
Do
not use
if dropped onto a hard surface.
o
Do
not remove
the Needle Cap until right before the injection.
Benlysta Prefilled Syringe Parts
Before use
After Use – Needle is covered by
Needle Guard
Supplies needed for the injection
Benlysta Prefilled Syringe
Alcohol Swab (not included)
Gauze Pad or Cotton Ball (not included)
Sharps Container (not included)
1 Gather and check supplies
Gather supplies
•
Remove 1 sealed tray containing a
prefilled syringe from the refrigerator.
•
Find a comfortable, well-lit, and
clean surface and place the following supplies within reach:
•
Benlysta Prefilled Syringe
•
Alcohol Swab (not included)
•
Gauze Pad or Cotton Ball (not
included)
•
Sharps Container (not included)
•
Do
not perform
the injection if you do not have all the supplies listed.
Check
expiration date
•
Peel back the film of the tray and
remove the prefilled syringe by holding the middle of the syringe body.
•
Check the expiration date on the
prefilled syringe. See Figure A
•
Do
not use
if the expiration date has passed.
2
Prepare and inspect the Benlysta Prefilled Syringe
Allow
to come to room temperature
•
Allow the prefilled syringe to sit at
room temperature for 30 minutes. See Figure B.
o
Do
not warm
the prefilled syringe in any other way. For example, do not warm in a microwave
oven, hot water, or in direct sunlight.
o
Do
not remove
the Needle Cap during this step.
Inspect
Benlysta solution
•
Look in the Inspection Window to
check that the Benlysta solution is colorless to slightly yellow in color. See
Figure C.
•
It is normal to see 1 or more air
bubbles in the solution.
•
Do
not use
if the solution looks cloudy, discolored, or has particles.
3
Choose and clean the injection site
Choose
the injection site
•
Choose where to inject (abdomen or
thigh). See Figure D.
•
Avoid injecting into the same site
each time or in areas where the skin is tender, bruised, red, or hard.
•
Do
not inject
within 2 inches of the belly button.
Clean
the injection site
•
Wash your hands.
•
Clean the injection site by wiping it
with an Alcohol Swab. Allow the skin to air dry. See Figure E.
•
Do
not touch
this area again before giving the injection
4 Prepare for the injection
Remove the Needle Cap
•
Do
not remove
the Needle Cap until right before you give the injection.
•
Hold the prefilled syringe by the
body, and with the Needle facing away from you. Remove the Needle Cap by
pulling it straight off. See Figure F.
You may see a drop of liquid at the
end of the Needle. This is normal.
•
Do
not let
the Needle touch any surface.
•
Do
not push
any air bubbles out of the prefilled syringe.
•
Do
not put
the Needle Cap back onto the prefilled syringe.
•
Keep
your hands away from the Plunger to avoid pushing it before injecting.
5 Inject Benlysta
Insert the Needle
•
Hold the prefilled syringe in one
hand and use your free hand to gently pinch the skin around the injection site.
See Figure G.
•
Insert the entire Needle into the
pinched area of the skin at a slight 45-degree angle using a dart-like motion.
•
After the Needle is completely
inserted, release the pinched skin.
Complete
the injection
•
Push the Plunger all the way down
until all of the solution is injected. See Figure H.
•
While keeping your hold on the
syringe, slowly move your thumb back, allowing the Plunger to rise up. The
Needle will automatically rise up into the Needle Guard. See Figure I.
6
Dispose of used prefilled syringe and inspect
Dispose
of the used prefilled syringe
Throw
away (dispose
of) the used syringe and Needle Cap in a Sharps Container. See Figure J.
•
Put your used syringe and sharps in
an FDA-cleared sharps disposal container right away after use. Do not throw
away (dispose of) loose needles and syringes in your household trash.
•
If you do not have a FDA-cleared
sharps disposal container, you may use a household container that:
o
is made of a heavy-duty plastic,
o
can be closed with a tight-fitting,
puncture-resistant lid, without sharps being able to come out,
o
is upright and stable during use,
o
is leak-resistant, and
o
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 safe sharps disposal, and for specific information about
sharps disposal in the state that you live in, go to: http://www.fda.gov/safesharpsdisposal.
•
Do
not dispose
of your used sharps disposal container in your household trash unless your
community guidelines permit this. Do not recycle your used sharps disposal
container.
Inspect
the injection site
•
There may be a small amount of blood
at the injection site. If needed, press a Cotton Ball or Gauze Pad on the
injection site.
•
Do
not rub
the injection site.
Additional
information
For more information about Benlysta,
go to www.Benlysta.com or call 1-877-423-6597.
This Instructions for Use has been
approved by the U.S. Food and Drug Administration.
Trademark is owned by or licensed to
the GSK group of companies.
Manufactured by Human Genome
Sciences, Inc., (a subsidiary of GlaxoSmithKline), Rockville, MD 20850
U.S.
License No. 1820
©2017 GSK
group of companies or its licensor.
BNL:1IFU-S
Approved
July 2017
PRINCIPAL DISPLAY PANEL
NDC 49401-101-01
Benlysta®
(belimumab)
for Injection
120 mg/vial
For
Intravenous Infusion after dilution only. Single-dose vial.
Discard
unused portion
Reconstitution: Reconstitute with 1.5 mL of Sterile Water for Injection,
USP. After reconstitution, the concentration of Benlysta is 80 mg/mL.
Dilute: Further
dilute in 250 mL of one of the following solutions before use:
•
0.9%
Sodium Chloride Injection, USP
•
0.45%
Sodium Chloride Injection, USP
•
Lactated
Ringer’s Injection, USP
Federal Law requires dispensing of Benlysta® with the Medication Guide
provided with this carton.
Rx only
©2016 the GSK group of companies
Rev. 6/16
10000000141921
PRINCIPAL DISPLAY PANEL
NDC 49401-102-01
Benlysta®
(belimumab)
for Injection
400 mg/vial
For Intravenous Infusion after dilution only. Single-dose vial.
Discard unused portion.
Reconstitution: Reconstitute with 4.8 mL of Sterile Water for Injection,
USP. After reconstitution, the concentration of Benlysta is 80 mg/mL.
Dilute: Further dilute in 250 mL of one of the following solutions
before use:
•
0.9%
Sodium Chloride Injection, USP
•
0.45%
Sodium Chloride Injection, USP
•
Lactated
Ringer’s Injection, USP
Federal Law requires dispensing of Benlysta® with the Medication Guide
provided with this carton.
Rx only
©2016 the GSK group of companies
Rev. 7/16
10000000141890
Click here to enter text.
PRINCIPAL DISPLAY PANEL
NDC 49401-088-35
Benlysta
(belimumab)
Injection
200 mg/vial
For Subcutaneous Use
Rx only
Contents:
•
4 Single-Dose 1-mL Prefilled Autoinjectors
•
Instructions for Use (Read carefully)
•
Medication Guide
•
Prescribing Information
Federal Law requires dispensing of Benlysta with the Medication
Guide provided with this package.
2017 GSK group of companies or is licensor.
Rev. 6/17
DEVCOMP-0004313
|
Benlysta belimumab injection, powder, lyophilized, for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:49401-102
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
BELIMUMAB (BELIMUMAB)
|
BELIMUMAB
|
400 mg
in 5 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
SODIUM CITRATE, UNSPECIFIED FORM
|
|
|
POLYSORBATE 80
|
|
|
CITRIC ACID MONOHYDRATE
|
|
|
SUCROSE
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:49401-102-01
|
1 VIAL in 1
CARTON
|
|
|
1
|
|
5 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA125370
|
03/10/2011
|
|
|
|
Benlysta belimumab injection, powder, lyophilized, for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:49401-101
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
BELIMUMAB (BELIMUMAB)
|
BELIMUMAB
|
120 mg
in 1.5 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CITRIC ACID MONOHYDRATE
|
|
|
SODIUM CITRATE, UNSPECIFIED FORM
|
|
|
SUCROSE
|
|
|
POLYSORBATE 80
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:49401-101-01
|
1 VIAL in 1
CARTON
|
|
|
1
|
|
1.5 mL in 1
VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA125370
|
03/10/2011
|
|
|
|
Benlysta belimumab solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:49401-088
|
|
Route of
Administration
|
SUBCUTANEOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
BELIMUMAB (BELIMUMAB)
|
BELIMUMAB
|
200 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
ARGININE HYDROCHLORIDE
|
|
|
HISTIDINE
|
|
|
HISTIDINE MONOHYDROCHLORIDE
|
|
|
POLYSORBATE 80
|
|
|
SODIUM CHLORIDE
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:49401-088-47
|
4 SYRINGE in 1
CARTON
|
|
|
1
|
NDC:49401-088-42
|
1 mL in 1
SYRINGE
|
|
|
2
|
NDC:49401-088-50
|
1 SYRINGE in 1
CARTON
|
|
|
2
|
NDC:49401-088-42
|
1 mL in 1
SYRINGE
|
|
|
3
|
NDC:49401-088-35
|
4 SYRINGE in 1
CARTON
|
|
|
3
|
NDC:49401-088-01
|
1 mL in 1
SYRINGE
|
|
|
4
|
NDC:49401-088-02
|
1 SYRINGE in 1
CARTON
|
|
|
4
|
NDC:49401-088-01
|
1 mL in 1
SYRINGE
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
BLA
|
BLA761043
|
07/20/2017
|
|
|
|
Labeler - Human Genome Sciences, Inc. (797057437)
|
Revised: 07/2017
Human Genome Sciences, Inc.
