Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Infusion-Related Reactions
Additions and/or
revisions underlined:
Intravenous or
subcutaneous administration of ULTOMIRIS may result in systemic
infusion-related reactions, including anaphylaxis [see Adverse Reactions
(6.3)] and hypersensitivity reactions. In clinical trials, infusion-related
reactions occurred in approximately 1 to 7% of patients treated with
ULTOMIRIS [see Adverse Reactions (6.1)]. These events
included lower back pain, abdominal pain, muscle spasms, drop in
blood pressure, elevation in blood pressure, rigors, limb discomfort,
drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and
drowsiness. These reactions did not require discontinuation of ULTOMIRIS. If
signs of cardiovascular instability or respiratory compromise occur, interrupt
ULTOMIRIS infusion and institute appropriate supportive measures.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Neuromyelitis Optica Spectrum Disorder (NMOSD)
Adult Population with NMOSD Treated with Intravenous ULTOMIRIS
The safety of ULTOMIRIS has been evaluated in 58
adult patients with NMOSD who received at least one dose of ULTOMIRIS
administered intravenously [see Clinical
Studies (14.3)]. In Study ALXN1210-NMO-307, an open-label multicenter
trial, the most frequent adverse reactions (greater than or equal to 10%) with
ULTOMIRIS were COVID-19, headache, back pain, urinary tract infection and
arthralgia.
Table 18 describes adverse reactions that occurred at a rate of 5% or more in
patients treated with ULTOMIRIS administered intravenously. Serious adverse
reactions were reported in 8 (13.8%) patients with NMOSD receiving ULTOMIRIS.
Table
18: Adverse Reactions Reported in greater
than or equal to 5% in Intravenous ULTOMIRIS- Treated Adult Patients with NMOSD
in Study ALXN1210-NMO-307
Please
refer to label to view Table 18.
8
Use in Specific Populations
8.4 Pediatric Use
Additions
and/or revisions underlined:
…
The
safety and effectiveness of ULTOMIRIS for the treatment of gMG or NMOSD
in pediatric patients have not been established.
…
8.5 Geriatric Use
Additions
and/or revisions underlined:
Clinical
studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65 and
over (58 patients with PNH, 9 with aHUS, 54 with gMG, and 7 with NMOSD)
to determine whether they respond differently from younger subjects.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
…
What is ULTOMIRIS?
ULTOMIRIS
is a prescription medicine called a monoclonal antibody. ULTOMIRIS is used to
treat:
…
adults with a disease called Neuromyelitis Optica
Spectrum Disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive.
…
It
is not known if ULTOMIRIS is safe and effective for the treatment of gMG or
NMOSD in children.
…
What are the
possible side effects of ULTOMIRIS?
…
The most common
side effects of ULTOMIRIS in people with NMOSD are:
COVID-19 infection
urinary tract infection
headache
joint pain (arthralgia)
back pain
…
Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined:
WARNING:
SERIOUS MENINGOCOCCAL INFECTIONS
ULTOMIRIS, a
complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and
Precautions (5.1)]. Life- threatening
and fatal meningococcal infections have occurred in patients treated with
complement inhibitors. These infections may become rapidly life- threatening or
fatal if not recognized and treated early.
Complete or update
vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at
least 2 weeks prior to the first dose of ULTOMIRIS, unless the risks of
delaying therapy with ULTOMIRIS outweigh the risk of developing a serious
infection. Comply with the most current Advisory Committee on Immunization
Practices (ACIP) recommendations for vaccinations against meningococcal
bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management
of the risk of serious infections caused by meningococcal bacteria.
Patients receiving
ULTOMIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they
develop antibodies following vaccination.
Monitor patients for early signs and symptoms of serious meningococcal
infections and evaluate immediately if infection is suspected.
Because of the
risk of serious meningococcal infections, ULTOMIRIS is available only through a
restricted program under a Risk Evaluation and Mitigation Strategy (REMS)
called ULTOMIRIS REMS [see Warnings and
Precautions (5.2)].
4
Contraindications
Additions
and/or revisions underlined:
ULTOMIRIS
is contraindicated for initiation in patients with unresolved serious
Neisseria
meningitidis infection
[see Warnings and Precautions (5.1)].
5
Warnings and Precautions
5.1 Serious Meningococcal Infections
Additions
and/or revisions underlined:
ULTOMIRIS,
a complement inhibitor, increases a patient’s susceptibility to serious, life-
threatening, or fatal infections caused by meningococcal bacteria (septicemia
and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and
fatal meningococcal infections have occurred in both vaccinated and
unvaccinated patients treated with complement inhibitors. The initiation
of ULTOMIRIS treatment is contraindicated in patients with unresolved
serious Neisseria meningitidis infection.
Complete
or update meningococcal vaccination (for serogroups A, C, W, Y and B) at
least 2 weeks prior to administration of the first dose of ULTOMIRIS,
according to current ACIP recommendations for patients receiving a complement
inhibitor.
Revaccinate
patients in accordance with ACIP recommendations considering the duration of
ULTOMIRIS therapy. Note that ACIP recommends an administration schedule in
patients receiving complement inhibitors that differs from the administration
schedule in the vaccine prescribing information. If urgent ULTOMIRIS therapy is
indicated in a patient who is not up to date with meningococcal vaccines
according to ACIP recommendations, provide the patient with antibacterial drug
prophylaxis and administer meningococcal vaccines as soon as possible. Various
durations and regimens of antibacterial drug prophylaxis have been considered,
but the optimal durations and drug regimens for prophylaxis and their efficacy
have not been studied in unvaccinated or vaccinated patients receiving
complement inhibitors, including ULTOMIRIS. The benefits and risks of treatment
with ULTOMIRIS, as well as the benefits and risks of antibacterial drug
prophylaxis in unvaccinated or vaccinated patients, must be considered against
the known risks for serious infections caused by Neisseria meningitidis.
Vaccination
does not eliminate the risk of meningococcal infections, despite development
of antibodies following vaccination.
Closely monitor
patients for early signs and symptoms of meningococcal infection and evaluate
patients immediately if infection is suspected. Inform patients of these signs
and symptoms and instruct patients to seek immediate medical care if these
signs and symptoms occur. Promptly treat known infections. Meningococcal
infection may become rapidly life-threatening or fatal if not recognized and
treated early. Consider interruption of ULTOMIRIS in patients who are
undergoing treatment for serious meningococcal infection, depending on the
risks of interrupting treatment in the disease being treated.
ULTOMIRIS
is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].
5.2 ULTOMIRIS REMS
Additions
and/or revisions underlined:
ULTOMIRIS
is available only through a restricted program under a REMS called ULTOMIRIS
REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1)].
Notable
requirements of the ULTOMIRIS REMS include the following:
Prescribers
must enroll in the REMS.
Prescribers
must counsel patients about the risk of meningococcal infection.
Prescribers
must provide the patients with the REMS educational materials.
Prescribers
must assess patient vaccination status for meningococcal vaccines (against
serogroups A, C, W, Y, and B) and vaccinate if needed according to current ACIP
recommendations two weeks prior to the first dose of ULTOMIRIS.
Prescribers must provide a prescription for antibacterial
drug prophylaxis if treatment must be started urgently and the patient is
not up to date with meningococcal vaccines according to current ACIP
recommendations at least two weeks prior to the first dose of ULTOMIRIS.
Patients
must receive counseling from the prescriber about the need to receive
meningococcal vaccines per ACIP recommendations, the need to take
antibiotics as directed by the prescriber, and the signs and symptoms of
meningococcal infection.
Patients must be instructed to carry the Patient
Safety Card with them at all times during and for 8 months following treatment
with ULTOMIRIS.
Further
information is available at www.ultomirisrems.com or
1-888-765-4747.
5.3 Other Infections
Additions
and/or revisions underlined:
Serious
infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal
infections, have been reported.
…
Administer
vaccinations for the prevention of Streptococcus
pneumoniae and Haemophilus influenzae
type b (Hib) infections according to ACIP recommendations. Patients
receiving ULTOMIRIS are at increased risk for infections due to these
organisms, even if they develop antibodies following vaccination.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Serious
Meningococcal Infections
Advise
patients of the risk of serious meningococcal infection. Inform patients
of the need to complete or update their meningococcal vaccinations at
least 2 weeks prior to receiving the first dose of ULTOMIRIS or receive
antibacterial drug prophylaxis if ULTOMIRIS treatment must be initiated
immediately and they have not been previously vaccinated. Inform
patients of the requirement to be revaccinated according to current ACIP
recommendations for meningococcal infection while on ULTOMIRIS therapy [see Warnings and Precautions (5.1)].
Inform
patients that vaccination may not prevent serious meningococcal
infection and to seek immediate medical attention if the following signs or
symptoms occur [see Warnings and
Precautions (5.1)]:
…
…
Inform
patients that they will be given a Patient Safety Card for ULTOMIRIS that they
should carry with them at all times during and for 8 months following
treatment with ULTOMIRIS. This card describes symptoms which, if
experienced, should prompt the patient to immediately seek medical evaluation.
ULTOMIRIS
REMS
ULTOMIRIS
is available only through a restricted program called ULTOMIRIS REMS
[see Warnings and
Precautions (5.2)].
Inform
the patient of the following notable requirements:
Patients
must receive counseling about the risk of serious meningococcal infections.
Patients
must receive written educational materials about this risk.
Patients
must be instructed to carry the Patient Safety Card with them at all times
during and for 8 months following treatment with ULTOMIRIS.
Patients
must be instructed to complete or update meningococcal vaccines for
serogroups A, C, W, Y and B per ACIP recommendations as directed by the
prescriber prior to treatment with ULTOMIRIS.
Patients must receive antibiotics as directed by the
prescriber if they are not up to date with meningococcal vaccines
and have to start ULTOMIRIS right away.
…
MEDICATION GUIDE
Additions
and/or revisions underlined:
What is the most
important information I should know about ULTOMIRIS?
…
…
Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined:
…
Because of the
risk of serious meningococcal infections,
ULTOMIRIS is available only through a restricted program under a Risk
Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS REMS [see Warnings and Precautions (5.2)].
5
Warnings and Precautions
5.1 Serious Meningococcal Infections
Additions and/or revisions
underlined
…
Immunize patients without a history of
meningococcal vaccination at least 2 weeks prior to receiving the first dose of
ULTOMIRIS. Patients who initiate ULTOMIRIS treatment less than 2
weeks after receiving meningococcal vaccine(s) must receive appropriate
prophylactic antibiotics until 2 weeks after vaccination.
…
Vaccination reduces, but does not eliminate, the
risk of meningococcal infections. In clinical studies with ULTOMIRIS, <
1% of patients developed serious meningococcal infections/sepsis while
receiving treatment with ULTOMIRIS. All were adult patients with PNH who
had been vaccinated. These patients recovered while continuing treatment with
ULTOMIRIS.
![]()
…
5.2 ULTOMIRIS REMS
Additions
and/or revisions underlined
ULTOMIRIS
is available only through a restricted program under a REMS called ULTOMIRIS
REMS, due to the risk of meningococcal infections [see Warnings and Precautions (5.2)].
Notable
requirements of the ULTOMIRIS REMS include the following:
Prescribers must enroll in the program
Prescribers
must counsel patients about the risk of meningococcal infection/sepsis
Prescribers must provide the patients with the REMS
educational materials
Prescribers must ensure patients are vaccinated
with meningococcal vaccines or receive 2 weeks of antibacterial drug
prophylaxis if treatment must be initiated immediately and vaccines are
administered less than 2 weeks before starting ULTOMIRIS
Patients must receive counseling from the prescriber,
take antibiotics as directed by the prescriber after vaccination (if they have
to start ULTOMIRIS right away), receive meningococcal vaccines as directed by
the prescriber, and carry the Patient Safety Card with them at all times during
and for 8 months following treatment with ULTOMIRIS.
![]()
Further
information is available at www.ultomirisrems.com or
1-888-765-4747.
5.7 Allergies to Acrylic Adhesives
New
subsection added
The
on-body injector of ULTOMIRIS uses acrylic adhesive. For patients with a known
allergy to acrylic adhesive, use of this product may result in an allergic
reaction.
Premedication
can be considered, and supportive measures should be instituted if signs of
allergy appear.
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
6.1 Clinical
Trials Experience
Extensive
additions and/or revisions, please refer to label for complete information.
6.2 Immunogenicity
Additions and/or revisions underlined
…
In patients receiving
subcutaneous administration of ULTOMIRIS (N = 128), no treatment-emergent
anti-drug antibodies were observed.
…
8
Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined
…
Subcutaneous administration of ULTOMIRIS has not
been evaluated and is not approved for use in pediatric patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined
…
ULTOMIRIS
REMS
ULTOMIRIS
is available only through a restricted program called ULTOMIRIS REMS
[see Warnings and
Precautions (5.2)].
Inform
the patient of the following notable requirements:
Patients must receive counseling about the risk of
serious meningococcal infections.
Patients must receive written educational materials
about this risk.
Patients must carry the Patient Safety Card with them
at all times during and for 8 months following treatment with ULTOMIRIS.
Patients must be vaccinated against meningococcal
disease prior to treatment with ULTOMIRIS or receive 2 weeks of antibacterial
drug prophylaxis if treatment must be initiated immediately and vaccines are
administered less than 2 weeks before starting ULTOMIRIS.
…
Allergies
to Acrylic Adhesives
Advise
patients that the single-use on-body injector used in subcutaneous
administration of ULTOMIRIS contains acrylic adhesive that may cause allergic
reactions to individuals sensitive to acrylic adhesives.
Administration
Provide
training to patients and caregivers on proper subcutaneous administration
technique and how to use the single-use on-body injector with prefilled
cartridge correctly.
Inform
patients that 2 on-body delivery systems (on-body injector with prefilled - cartridge)
are required for a full dose.
Additionally,
inform patients that it will take about 10 minutes to administer each ULTOMIRIS
on-body delivery system for subcutaneous administration.
The
single-use on-body injector with prefilled cartridge is not made with natural
rubber latex.
MEDICATION GUIDE
Extensive
additions and/or revisions; please refer to label for complete information.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Serious Meningococcal Infections
![]()
Additions underlined
…
In clinical studies, 59 adult patients with PNH and
2 adult patients with gMG were treated with ULTOMIRIS less than 2 weeks
after meningococcal vaccination. All of these patients received antibiotics for
prophylaxis of meningococcal infection until at least 2 weeks after
meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for
prevention of meningococcal infections in patients receiving ULTOMIRIS have not
been established.
![]()
…
5.5 Infusion-Related Reactions
Additions and/or revisions
underlined
Administration of ULTOMIRIS may result in
infusion-related reactions, including anaphylaxis [see Adverse Reactions (6.3)]
and hypersensitivity reactions. In clinical trials, infusion-related
reactions occurred in approximately 1% of patients treated with ULTOMIRIS. These
events included lower back pain, drop in blood pressure, elevation in blood
pressure, limb discomfort, drug hypersensitivity (allergic reaction),
dysgeusia (bad taste), and drowsiness. These reactions did not require discontinuation
of ULTOMIRIS. If signs of cardiovascular instability or respiratory compromise
occur, interrupt ULTOMIRIS infusion and institute appropriate supportive
measures.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions underlined
Generalized Myasthenia Gravis (gMG)
Adult Population with gMG
The safety of ULTOMIRIS has been evaluated in 175
adult patients with gMG, including 169 patients who received at least one dose
of ULTOMIRIS, 142 patients who were exposed for at least 6 months, and 95 who
were exposed for at least 12 months [see
Clinical Studies (14.3)]. In a randomized, double-blind, placebo-controlled
trial (ALXN1210-MG-306), the most frequent adverse reactions (greater than or
eqal to 10%) with ULTOMIRIS were diarrhea and upper respiratory tract
infection. Table 14 describes adverse reactions that occurred at a rate of 5% or more and at
greater frequency than placebo. Serious adverse reactions were reported in 20
(23%) patients with gMG receiving ULTOMIRIS and in 14 (16%) patients receiving
placebo. The most frequent serious adverse reactions were infections reported
in at least 8 (9%) patients treated with ULTOMIRIS and in 4 (4%) patients
treated with placebo [see Warnings and
Precautions (5.2)]. Of these infections, one fatal case of COVID-19
pneumonia was identified in a patient treated with ULTOMIRIS and one case of
infection led to discontinuation of ULTOMIRIS.
Table 14: Adverse
Reactions Reported in greater than or equal to 5% and at Greater Frequency than
Placebo in ULTOMIRIS-Treated Adult Patients with gMG in Study ALXN1210-MG-306
Please refer to label to view Table 14
6.2 Immunogenicity
Additions underlined
…
No treatment-emergent antibodies to ravulizumab-cwvz
were detected in patients with gMG treated with ULTOMIRIS.
…
7
Drug Interactions
7.1 Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins
New
subsection added
Concomitant
use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous
immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and
requires a supplemental dose of ULTOMIRIS [see
Dosage and Administration (2.3)].
7.2 Neonatal Fc Receptor Blockers
New
subsection added
Concomitant
use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod)
may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely
monitor for reduced effectiveness of ULTOMIRIS.
8
Use in Specific Populations
8.4 Pediatric Use
Additions
underlined
…
Safety
and effectiveness of ULTOMIRIS for the treatment of gMG in pediatric patients
have not been established.
8.5 Geriatric Use
Additions underlined
Clinical studies of ULTOMIRIS did not include
sufficient numbers of subjects aged 65 and over (58 patients with PNH, 9
with aHUS, and 54 with gMG) to determine whether they respond differently
from younger subjects.
Other reported clinical experience has not
identified differences in responses between elderly and younger patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined
…
Inform
patients who discontinue ULTOMIRIS to keep the ULTOMIRIS Patient Safety Card
with them for eight months after the last ULTOMIRIS dose, because the increased
risk of meningococcal infection persists for several months following
discontinuation of ULTOMIRIS.
…
MEDICATION GUIDE
Additions underlined
…
What is ULTOMIRIS?
ULTOMIRIS
is a prescription medicine called a monoclonal antibody. ULTOMIRIS is used to
treat:
adults
and children 1 month of age and older with a disease called Paroxysmal
Nocturnal Hemoglobinuria (PNH).
adults
and children 1 month of age and older with a disease called atypical hemolytic
uremic syndrome (aHUS).
ULTOMIRIS is not used in treating people
with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
adults
with a disease called generalized myasthenia gravis (gMG) who are anti-acetylcholine
receptor (AChR) antibody positive.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Serious Meningococcal Infections
(Additions and/or
revisions underlined)
Risk and Prevention
Life-threatening meningococcal infections have
occurred in patients treated with ULTOMIRIS. The use of ULTOMIRIS increases a
patient’s susceptibility to serious meningococcal infections (septicemia and/or
meningitis). Meningococcal disease due to any serogroup may occur.
Vaccinate for meningococcal disease according to the
most current Advisory Committee on Immunization Practices (ACIP)
recommendations for patients with complement deficiencies. Revaccinate patients
in accordance with ACIP recommendations considering the duration of ULTOMIRIS
therapy.
Immunize patients without a history of meningococcal
vaccination at least 2 weeks prior to receiving the first dose of ULTOMIRIS. If
urgent ULTOMIRIS therapy is indicated in an unvaccinated patient, administer
meningococcal vaccine(s) as soon as possible and provide patients with 2 weeks
of antibacterial drug prophylaxis.
In clinical studies, 59 adult patients with
PNH were treated with ULTOMIRIS less than 2 weeks after meningococcal
vaccination. All of these patients received antibiotics for prophylaxis of
meningococcal infection until at least 2 weeks after meningococcal vaccination.
The benefits and risks of antibiotic prophylaxis for prevention of
meningococcal infections in patients receiving ULTOMIRIS have not been
established.
Vaccination reduces, but does not eliminate, the
risk of meningococcal infections. In PNH clinical studies in adult patients,
3 out of 261 PNH patients developed serious meningococcal infections/sepsis
while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3
patients recovered while continuing treatment with ULTOMIRIS. In the PNH
study in pediatric patients, no meningococcal infections occurred among the 13
patients receiving treatment with ULTOMIRIS.
Closely monitor patients for early signs and
symptoms of meningococcal infection and evaluate patients immediately if
infection is suspected. Inform patients of these signs and symptoms and steps
to be taken to seek immediate medical care. Meningococcal infection may become
rapidly life-threatening or fatal if not recognized and treated early. Consider
discontinuation of ULTOMIRIS in patients who are undergoing treatment for
serious meningococcal infection.
REMS
Due to the risk of meningococcal infections, ULTOMIRIS
is available only through a restricted program under a Risk Evaluation and
Mitigation Strategy (REMS). Under the ULTOMIRIS REMS, prescribers must enroll
in the program.
Prescribers must counsel patients about the risk of
meningococcal infection/sepsis, provide the patients with the REMS educational
materials, and ensure patients are vaccinated with meningococcal vaccines.
Enrollment in the ULTOMIRIS REMS and additional
information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com.
5.5 Infusion-Related Reactions
(Additions and/or
revisions underlined)
Administration of ULTOMIRIS may result in
infusion-related reactions. In clinical trials, 4 out of 309
patients treated with ULTOMIRIS experienced infusion-related reactions (lower
back pain, drop in blood pressure, elevation in blood pressure and limb
discomfort) during ULTOMIRIS administration. These reactions did not require
discontinuation of ULTOMIRIS. Interrupt ULTOMIRIS infusion and institute
appropriate supportive measures if signs of cardiovascular instability or
respiratory compromise occur.
6
Adverse Reactions
6.1 Clinical Trial Experience
(Extensive
changes; please refer to label)
6.2 Immunogenicity
(Additions and/or
revisions underlined)
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 antibodies) 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 in the
studies described below with the incidence of antibodies in other studies or to
other ravulizumab- cwvz products may be misleading.
The immunogenicity of ravulizumab-cwvz has been
evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection
of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested
positive in the screening immunoassay, an in vitro biological assay was
performed to detect neutralizing antibodies.
In clinical studies, treatment-emergent antibodies
to ravulizumab-cwvz were detected in 1 of 219 (0.5%) patients with PNH
and 1 of 71 (1.4%) patients with aHUS. In these 2 patients, no apparent
correlation of antibody development to altered pharmacokinetic profile,
clinical response, or adverse events was observed. However, the assay used
to measure anti-drug antibodies (ADA) is subject to interference by serum
ravulizumab- cwvz, possibly resulting in an underestimation of the incidence of
antibody formation. Due to the limitation of the assay conditions, the
potential clinical impact of antibodies to ravulizumab-cwvz is not known.
8
Use in Specific Populations
8.4 Pediatric Use
(Additions and/or
revisions underlined)
The
safety and effectiveness of ULTOMIRIS for the treatment of PNH have been
established in pediatric patients aged one month and older. Use of ULTOMIRIS
for this indication is supported by evidence from adequate and well-controlled
trials in adults with additional pharmacokinetic, efficacy and safety data in
pediatric patients aged 9 to 17 years [see
Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies
(14.1)]. The safety and efficacy for the treatment of pediatric and adult
patients with PNH appear similar. Use of ULTOMIRIS in pediatric patients with PNH
aged less than 9 years and body weight <30 kg is based on extrapolation of
pharmacokinetic / pharmacodynamic (PK/PD), and efficacy and safety data from
aHUS and PNH clinical studies [see
Clinical Pharmacology (12.3) and Clinical Studies (14)].
The
safety and effectiveness of ULTOMIRIS for the treatment of aHUS have been
established in pediatric patients aged one month and older. Use of ULTOMIRIS
for this indication is supported by evidence from adequate and well-controlled
studies in adults with additional pharmacokinetic, safety, and efficacy data in
pediatric patients aged 10 months to <17 years. The safety and efficacy of
ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult
patients [see Adverse Reactions (6.1),
and Clinical Studies (14.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
What is ULTOMIRIS?
ULTOMIRIS
is a prescription medicine called a monoclonal antibody. ULTOMIRIS is used to
treat:
- adults
and children 1 month of age and older with a disease called atypical hemolytic
uremic syndrome (aHUS).
ULTOMIRIS
is not used in treating people with Shiga toxin E. coli related hemolytic uremic
syndrome (STEC-HUS).
It
is not known if ULTOMIRIS is safe and effective in children younger than 1
month of age.
…
How should I
receive ULTOMIRIS?
- ULTOMIRIS is given
through a vein by intravenous (I.V.) infusion
If you are an
adult with PNH or aHUS, you will usually receive:
- 2
weeks later, you will start to receive an infusion of ULTOMIRIS every 8 weeks.
Children 1 month
of age and older with PNH or aHUS will usually receive:
- your
doctor will decide how often your child will receive ULTOMIRIS, either every 4
weeks or every 8 weeks, depending on their weight, starting 2 weeks after the
starting dose.
Your
doctor will decide how long you need to take ULTOMIRIS for your PNH or your
aHUS.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Infusion-Related Reactions
(Subsection title
revised; Additions and/or revisions underlined)
Administration
of ULTOMIRIS may result in infusion-related reactions. In clinical
trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion-related
reactions (lower back pain, drop in blood pressure, infusion-related pain,
elevation in blood pressure and limb discomfort) during ULTOMIRIS administration.
These reactions did not require discontinuation of ULTOMIRIS. Interrupt
ULTOMIRIS infusion and institute appropriate supportive measures if signs of
cardiovascular instability or respiratory compromise occur.
6
Adverse Reactions
(Additions and/or revisions underlined)
The
following clinically significant adverse reactions are discussed in greater
detail in other sections of the labeling:
- Serious Meningococcal
Infections [see Warnings and
Precautions (5.1)]
- Other Infections [see Warnings and Precautions (5.2)]
- Infusion-Related
Reactions [see Warnings and
Precautions (5.5)]
6.1 Clinical Trial Experience
(Extensive changes;
please refer to label)
6.2 Immunogenicity
(Additions and/or revisions underlined)
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 antibodies) 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 in the studies described below with
the incidence of antibodies in other studies or to other ravulizumab products
may be misleading.
The
immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked
immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz
antibodies. For patients whose sera tested positive in the screening
immunoassay, an in vitro biological assay was performed to detect neutralizing
antibodies.
In
clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were
detected in 1 of 206 (0.5%) patients with PNH and 1 of 71 (1.4%) patients with
aHUS. No apparent correlation of antibody development to altered
pharmacokinetic profile, clinical response, or adverse reactions was
observed.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or revisions underlined)
…
ULTOMIRIS is only
available through a program called the ULTOMIRIS REMS. Before you can
receive ULTOMIRIS, your doctor must:
enroll
in the ULTOMIRIS REMS program
counsel
you about the risk of meningococcal infection
give
you information about the symptoms of meningococcal infection
give
you a Patient Safety Card about your
risk of meningococcal infection, as discussed above
make
sure that you are vaccinated with a meningococcal vaccine, and if needed,
get revaccinated with the meningococcal vaccine. Ask your doctor if you are not
sure if you need to be revaccinated.
ULTOMIRIS may also
increase the risk of other types of serious infections.
People
who take ULTOMIRIS may have an increased risk of getting infections caused by Streptococcus pneumoniae and Haemophilus influenzae.
- Certain
people may also have an increased risk of gonorrhea infection. Talk to your
doctor to find out if you are at risk for gonorrhea infection, about gonorrhea
prevention, and regular testing.
Call
your doctor right away if you have any new signs or symptoms of infection.
…
What are the
ingredients in ULTOMIRIS?
Active ingredient: ravulizumab-cwvz
Inactive
ingredients:
ULTOMIRIS 100
mg/mL:
L-arginine, polysorbate 80 (vegetable origin), sodium phosphate dibasic, sodium
phosphate monobasic, sucrose and Water for Injection
ULTOMIRIS 10 mg/mL: polysorbate 80 (vegetable origin),
sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic and Water
for Injection
PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
Advise
the patient to read FDA-approved patient labeling (Medication Guide).
Meningococcal
Infection
Advise
patients of the risk of meningococcal infection/sepsis. Inform patients that
they are required to receive meningococcal vaccination at least 2 weeks prior
to receiving the first dose of ULTOMIRIS, if they have not previously been
vaccinated. They are required to be
revaccinated according to current medical guidelines for meningococcal vaccines
use while on ULTOMIRIS therapy. Inform patients that vaccination may not
prevent meningococcal infection. Inform patients about the signs and symptoms
of meningococcal infection/sepsis, and strongly advise patients to seek
immediate medical attention if these signs or symptoms occur. These signs and
symptoms are as follows:
- headache
with nausea or vomiting
Inform
patients that they will be given an ULTOMIRIS Patient Safety Card that they
should carry with them at all times. This card describes symptoms which, if
experienced, should prompt the patient to immediately seek medical evaluation.
Other
Infections
Counsel
patients of the increased risk of infections, particularly those due to
encapsulated bacteria, especially Neisseria
species. Advise patients of the need for vaccination against meningococcal
infections according to current medical guidelines. Counsel patients about
gonorrhea prevention and advise regular testing for patients at risk. Advise
patients to report any new signs and symptoms of infection.
Discontinuation
Inform
patients with PNH or aHUS that they may develop hemolysis or TMA, respectively,
when ULTOMIRIS is discontinued and that they will be monitored by their
healthcare professional for at least 16 weeks for PNH or at least 12 months for
aHUS following ULTOMIRIS discontinuation.
Inform
patients who discontinue ULTOMIRIS to keep the ULTOMIRIS Patient Safety Card
with them for eight months after the last ULTOMIRIS dose, because the increased
risk of meningococcal infection persists for several weeks following
discontinuation of ULTOMIRIS.
Infusion-Related
Reactions
Advise
patients that administration of ULTOMIRIS may result in infusion-related
reactions.
Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
ULTOMIRIS is contraindicated in:
·
Patients who
are not currently vaccinated against Neisseria meningitidis, unless
the risks of delaying ULTOMIRIS
treatment outweigh the risks of developing
a meningococcal
infection
5
Warnings and Precautions
Infusion Reactions
Additions and/or revisions underlined:
Administration of
ULTOMIRIS may result in infusion reactions. In clinical
trials,
5 out of
296
patients treated with ULTOMIRIS
experienced infusion reactions (lower back pain, drop in blood pressure, infusion-related pain,
elevation in blood pressure and limb discomfort) during ULTOMIRIS administration.
Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
Additions and/or revisions underlined:
Treatment Discontinuation for PNH
After
discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms
of hemolysis, identified by elevated LDH along with sudden decrease in PNH
clone size or hemoglobin, or re-appearance
of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath
(dyspnea), major adverse vascular event (including thrombosis),
dysphagia, or erectile dysfunction. Monitor
any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions. If signs and symptoms
of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment
with ULTOMIRIS.
Treatment Discontinuation for aHUS
ULTOMIRIS
treatment of aHUS should be a minimum
duration of 6 months. Due to heterogeneous
nature of aHUS events and patient-specific risk factors, treatment
duration beyond the initial 6 months should
be individualized.
There are no specific data on ULTOMIRIS discontinuation.
After
discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and
laboratory signs of TMA complications for at least 12 months.
TMA complications post-discontinuation
can be identified if any of the following is observed:
· Clinical
symptoms of TMA include changes in mental status, seizures, angina, dyspnea,
thrombosis or increasing blood
pressure.
·
In addition, at least two of the following laboratory signs observed
concurrently and results should be confirmed
by a second measurement 28 days apart
with no interruption
o
a decrease in platelet count of 25% or more
as compared to either baseline or to peak platelet count
during ULTOMIRIS treatment;
o
an increase in serum creatinine of 25% or more as compared
to baseline or to
nadir during ULTOMIRIS treatment;
o
an increase in serum LDH of 25% or more as
compared to baseline or to nadir
during ULTOMIRIS treatment.
If
TMA complications occur after ULTOMIRIS
discontinuation, consider
reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.
Other Infections
Additions and/or revisions underlined:
ULTOMIRIS
blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated
bacteria infections, especially infections
caused by Neisseria meningitidis but
also Streptococcus
pneumoniae, Haemophilus influenzae, and to a lesser extent,
Neisseria gonorrhoeae. Children treated with ULTOMIRIS may be at
increased risk of developing serious
infections due to Streptococcus
pneumoniae and Haemophilus influenzae type b
(Hib). Administer vaccinations for the prevention of Streptococcus
pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. If
ULTOMIRIS therapy is administered to patients
with active systemic infections, monitor
closely for signs and symptoms of
worsening infection.
6
Adverse Reactions
Clinical Trial Experience
Newly added
subsection:
Atypical Hemolytic Uremic Syndrome
(aHUS)
The data described below reflect exposure of 58 adult and 16 pediatric patients with aHUS in
single-arm trials who received ULTOMIRIS at the recommended
dose and schedule. The most
frequent adverse reactions reported in ?20%
of patients treated with ULTOMIRIS
were upper respiratory tract infection,
diarrhea, nausea, vomiting, headache, hypertension and pyrexia. Tables 6, 7 and 8
describes adverse reactions that occurred
at a rate of 10% or more among
patients treated with ULTOMIRIS in aHUS studies. Serious adverse reactions were reported in 42 (57%) patients with
aHUS receiving ULTOMIRIS. The most frequent serious
adverse reactions reported in more than 2 patients (2.7%) treated with ULTOMIRIS were hypertension, pneumonia and abdominal
pain. Four patients died during the
ALXN1210-aHUS-311 study. The cause of
death was sepsis in two patients and
intracranial hemorrhage in one
patient. The fourth patient,
who was excluded from the trial after a diagnosis of STEC-HUS, died due to pretreatment cerebral arterial thrombosis.
Addition of Tables 6,
7, and 8: Adverse Reactions Reported
in ?10% of ULTOMIRIS-Treated Patients with
aHUS in three studies
Immunogenicity
Additions and/or revisions underlined:
In clinical studies, treatment-emergent
antibodies to ravulizumab-cwvz were
detected in 1 of 206 (0.5%) patients
with PNH and 1 of 71 (1.4%)
patients with aHUS.
8
Use in Specific Populations
Pediatric Use
Additions and/or revisions underlined:
The safety and efficacy of ULTOMIRIS for the treatment of PNH in pediatric patients have not been established.
The safety and
effectiveness of ULTOMIRIS for the treatment
of aHUS have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients aged 10 months
to <17 years. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar
in pediatric and adult patients.
Pregnancy
Additions and/or revisions underlined:
There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy. . . In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and
preterm delivery, and adverse
fetal/neonatal outcomes, including intrauterine
growth restriction (IUGR), fetal death and low birth weight.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or
revisions underlined:
What is ULTOMIRIS?
ULTOMIRIS is a prescription medicine called a monoclonal
antibody. ULTOMIRIS is used to treat:
• adults
with a disease called Paroxysmal Nocturnal Hemoglobinuria (PNH).
• adults
and children 1 month of age and older with a disease called atypical hemolytic
uremic syndrome (aHUS). ULTOMIRIS is not used in treating people with Shiga
toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
It is not known if ULTOMIRIS is safe and effective in children
with PNH.
It is not known if ULTOMIRIS is safe and effective in
children younger than 1 month of age.
Who should not receive ULTOMIRIS? Do not receive
ULTOMIRIS if you:
• have a
meningococcal infection
• have
not been vaccinated against meningococcal infection unless your doctor decides
that urgent treatment with ULTOMIRIS is needed. See ”What is the most important
information I should know about ULTOMIRIS.”
How should I receive ULTOMIRIS?
• ULTOMIRIS
is given through a vein by intravenous (I.V.) infusion usually over about 2
hours in adults and up to 4 hours in children.
If you are an adult with PNH or aHUS, you will
usually receive:
• a
starting dose of ULTOMIRIS as an infusion by your doctor, and then
• 2 weeks
later, you will start to receive an infusion of ULTOMIRIS every 8 weeks.
Children 1 month of age and older with aHUS will usually
receive:
• a
starting dose of ULTOMIRIS as an infusion by your doctor, and then
• your
doctor will decide how often your child will receive ULTOMIRIS, either every 4
weeks or every 8 weeks, depending on their weight, starting 2 weeks after the
starting dose.
Your doctor will decide how long you need to take
ULTOMIRIS for your aHUS.
• If you
are changing treatment from SOLIRIS to ULTOMIRIS, you should receive your
starting dose of ULTOMIRIS 2 weeks after your last dose of SOLIRIS.
• After
each infusion, you should be monitored for at least 1 hour for infusion
reactions. See “What are the possible side effects of ULTOMIRIS?”
• If you
have PNH and you stop receiving ULTOMIRIS, your doctor will need to monitor
you closely for at least 16 weeks after you stop ULTOMIRIS. Stopping ULTOMIRIS
may cause breakdown of your red blood cells due to PNH.
Symptoms or problems that can happen due to red blood cell
breakdown include:
o drop in
your red blood cell count o shortness of breath
o tiredness o
blood clots
o blood in
your urine o trouble swallowing
o stomach-area
(abdomen) pain o erectile dysfunction (ED) in males
• If you
have aHUS, your doctor will need to monitor you closely for at least 12 months
after stopping treatment for signs of worsening aHUS or problems related to a
type of abnormal clotting and breakdown of your red blood cells called
thrombotic microangiopathy (TMA).
Symptoms or problems that can happen with TMA may
include:
o confusion
or loss of consciousness o difficulty breathing
o seizures o blood clots or stroke
o chest
pain (angina)
The most common side effects of ULTOMIRIS in people
treated for PNH are upper respiratory infection and headache.
The most common side effects of ULTOMIRIS in people with
aHUS are:
• upper
respiratory infections • headache
• diarrhea • high
blood pressure
• nausea • fever
• vomiting
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
Inform
patients with PNH or aHUS that they may develop hemolysis
or TMA, respectively, when ULTOMIRIS is discontinued and that they will
be monitored by their healthcare
professional for at least 16
weeks for PNH or at least 12 months for aHUS following ULTOMIRIS discontinuation.
Get Email Alerts |
Guide
