WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA
VOYDEYA, a complement inhibitor, increases the risk of
serious
infections, especially those
caused by encapsulated bacteria, such as
Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type B [see Warnings and Precautions (5.1)]. Life-threatening and fatal infections with encapsulated
bacteria 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 encapsulated bacteria
specifically, Neisseria meningitidis and
Streptococcus pneumoniae at least 2 weeks prior to the first dose of VOYDEYA, unless
the risks
of delaying therapy with VOYDEYA outweigh the
risk of developing a serious infection. Comply with the most
current Advisory Committee on Immunization Practices (ACIP)
recommendations for vaccinations against encapsulated 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 encapsulated bacteria.
Patients receiving VOYDEYA are at increased risk for
invasive disease
caused by encapsulated bacteria, even
if they develop antibodies following vaccination. Monitor patients
for early signs and symptoms
of
serious
infections and evaluate immediately if infection
is
suspected.
Because of the risk of serious infections caused by
encapsulated bacteria,
VOYDEYA is available only through
a restricted program under
a Risk Evaluation
and Mitigation Strategy (REMS) called the VOYDEYA REMS [see Warnings and Precautions (5.2)].
CONTRAINDICATIONS
Initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae type B.
WARNINGS AND PRECAUTIONS
Serious Infections Caused by Encapsulated Bacteria
VOYDEYA, a complement inhibitor, increases a patient’s
susceptibility to serious, life-threatening, or fatal infections
caused by encapsulated bacteria, including
Neisseria meningitidis (caused by any serogroup,
including non-groupable strains),
Streptococcus pneumoniae, and Haemophilus influenzae
type
B. Life-threatening and fatal infections with encapsulated
bacteria have occurred in both vaccinated and unvaccinated patients
treated with complement inhibitors.
Complete, update, or revaccinate patients in accordance with
ACIP recommendations considering the duration of VOYDEYA
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 VOYDEYA therapy is indicated in a patient who is not
up to date with vaccines against encapsulated bacteria according
to ACIP recommendations, provide antibacterial drug prophylaxis
and administer these 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 VOYDEYA. The benefits and risks of treatment
with VOYDEYA, as well as those associated with antibacterial drug
prophylaxis in unvaccinated or vaccinated patients, must be considered
against the known risks for serious infections caused by encapsulated
bacteria.
Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if they occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of VOYDEYA in patients who are undergoing treatment for serious infections.
VOYDEYA REMS
Due to the risk of serious infections caused by encapsulated
bacteria, VOYDEYA is available only through a restricted program
called VOYDEYA
REMS. Per the REMS requirements:
Prescribers must enroll in the REMS, counsel patients about the
risk of serious infections caused by encapsulated bacteria,
provide patients with the REMS educational materials, assess
patient vaccination status for vaccines against encapsulated
bacteria, and vaccinate if needed according to current ACIP
recommendations 2 weeks prior to the first
dose of VOYDEYA.
Antibacterial drug prophylaxis must be prescribed if treatment must
be started urgently and the patient is not up to date with vaccines
against encapsulated bacteria according to current ACIP recommendations
at least 2 weeks prior to the first dose of VOYDEYA.
Pharmacies that dispense VOYDEYA must be certified in the VOYDEYA REMS and must verify prescribers are certified.
Patients must receive counseling from the prescriber about the
need to
receive vaccinations against encapsulated
bacteria per ACIP recommendations, to take antibiotics as directed,
the early signs and symptoms of serious infection, and be instructed
to carry the Patient Safety Card at all times during and for 1 week
following the last dose of VOYDEYA.
Further information is available at www.voydeyarems.com or 1-888-765-4747.
Hepatic Enzyme Increases
Hepatic enzyme elevations have been observed in patients treated
with VOYDEYA. A total of
14% of patients receiving VOYDEYA
had elevations in serum alanine aminotransferase (ALT). ALT elevations
>3× the upper limit of normal (ULN) and ≤5× ULN occurred in 9% of
VOYDEYA-treated patients, and ALT elevations >5× ULN and ≤10× ULN
occurred in 5% of VOYDEYA-treated patients.
Assess liver enzyme test results prior to the initiation of VOYDEYA and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or if the patient becomes symptomatic. VOYDEYA has not been studied in patients with severe hepatic impairment.
Monitoring of PNH Manifestations After VOYDEYA Discontinuation
After discontinuing treatment with VOYDEYA, closely monitor
patients for at least 2 weeks after the last dose for signs and
symptoms of hemolysis. If discontinuation of VOYDEYA is
necessary, continue background treatment
with ravulizumab or eculizumab or consider alternative therapy
if necessary. The signs and symptoms of hemolysis may include sudden
decrease in hemoglobin or fatigue.
If hemolysis occurs after discontinuation of VOYDEYA, consider restarting treatment with VOYDEYA, if appropriate.
Hyperlipidemia
VOYDEYA increases total cholesterol and LDL-cholesterol. Of the
50
VOYDEYA-treated
patients who
had a normal total cholesterol
level at baseline, 30% developed Grade 1 hypercholesterolemia. Of
the 6 VOYDEYA-treated patients who had Grade 1 hypercholesterolemia
at baseline, 1 patient experienced increased total cholesterol that
worsened to Grade 2. Of the 54 VOYDEYA-treated patients who had LDL-cholesterol
≤130 mg/dL at baseline, 13% developed LDL-cholesterol >130-160 mg/dL,
and 9% developed LDL-cholesterol >160-190 mg/dL.
Some patients required cholesterol-lowering medications. Monitor
serum lipid parameters periodically during treatment with
VOYDEYA
and initiate cholesterol-lowering medication, if indicated.
ADVERSE REACTIONS
The most common adverse reaction reported in ≥10% of patients treated with VOYDEYA was headache. Serious adverse reactions were reported in 5% of patients who received VOYDEYA and included pancreatitis, cholecystitis, and increased blood bilirubin. No specific serious adverse reaction was reported in more than 1 patient treated with VOYDEYA. Adverse reactions reported in ≥5% of patients treated with VOYDEYA and greater than placebo in the randomized, controlled period included vomiting, pyrexia, increased alanine aminotransferase, hypertension, and pain in the extremities. Clinically relevant adverse reactions in <5% of patients included increased serum triglycerides.
DRUG INTERACTIONS
BCRP Substrates
Danicopan is a Breast Cancer Resistance Protein (BCRP)
inhibitor.
Concomitant use of VOYDEYA
with a BCRP substrate increases the plasma concentrations of the
BCRP substrate, which may increase the risk for adverse reactions
associated with the BCRP substrate.
If used together, monitor
patients more frequently for adverse reactions, associated
with the BCRP substrate and consider dose reduction of the BCRP substrate
according to
its prescribing information.
Rosuvastatin
Danicopan significantly increased rosuvastatin exposure. The
dose of rosuvastatin should not exceed 10mg once daily when
concomitantly used
with VOYDEYA.
P-glycoprotein Substrates
Danicopan is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of VOYDEYA with P-gp substrates may increase the plasma concentrations of the P-gp substrates. Dose adjustment might be necessary for P-gp substrates where minimal concentration changes may lead to serious adverse reactions.
USE IN SPECIFIC POPULATIONS
Pregnancy
There are no available data on VOYDEYA use in pregnant
individuals to
evaluate for a drug-associated
risk of major birth defects, miscarriage, or adverse maternal or
fetal outcomes. There are risks to the mother and fetus associated
with untreated PNH in pregnancy. The use of VOYDEYA in pregnant women
or women planning to become pregnant may be considered following
an assessment of the risks and benefits.
Lactation
There are no data on the presence of VOYDEYA in human milk, the
effects on the breastfed
child, or the effect on milk production.
VOYDEYA is present in animal milk. When a
drug is present
in animal milk, it is likely that the drug will be present in human
milk.
Because of the potential for
serious adverse reactions in the breastfed child, including serious
infections with encapsulated bacteria and liver enzyme increases,
advise patients not to breastfeed during treatment with VOYDEYA and
for 3 days after the last dose.
Hepatic Impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. Studies have not been conducted in patients with severe hepatic impairment, therefore, avoid use of VOYDEYA in this patient population.
INDICATION
VOYDEYA is indicated as an add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH).
Limitation of Use:
VOYDEYA has not been shown to be effective
as monotherapy and
should only be prescribed
as an add-on to ravulizumab or eculizumab.
To report SUSPECTED ADVERSE REACTIONS, contact Alexion
Pharmaceuticals, Inc. at
1-844-259-6783 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information for VOYDEYA, including Boxed WARNING
regarding serious
and life-threatening or
fatal infections.
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 ULTOMIRIS therapy 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 and SOLIRIS REMS [see Warnings and Precautions (5.2)].
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
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.
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
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 those associated with 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 serious 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
they 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 and SOLIRIS REMS
Due to the risk of serious meningococcal infections, ULTOMIRIS
is available only through
a restricted program called ULTOMIRIS
and SOLIRIS REMS.
Prescribers must enroll in the REMS, counsel patients about the risk of serious meningococcal infection, provide patients with the REMS educational materials, 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. Antibacterial drug prophylaxis must be prescribed if treatment must be started urgently, and the patient is not up to date with both meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of ULTOMIRIS. Patients must receive counseling about the need to receive meningococcal vaccines and to take antibiotics as directed, signs and symptoms of meningococcal infection, and be instructed to carry the Patient Safety Card at all times during and for 8 months following ULTOMIRIS treatment.
Further information is available at www.UltSolREMS.com or
1-888-765-4747.
Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.
ULTOMIRIS blocks terminal complement activation; therefore,
patients may have increased susceptibility to infections,
especially with encapsulated bacteria, such as 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 recommendations. Patients receiving ULTOMIRIS are at increased
risk for infections due to these organisms, even if they develop
antibodies following vaccination.
Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
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.
Thromboembolic Event Management
The effect of withdrawal of anticoagulant therapy during
treatment with ULTOMIRIS has
not been established. Treatment
should not
alter anticoagulant management.
Infusion-Related Reactions
Intravenous administration may result in systemic
infusion-related
reactions, including
anaphylaxis and hypersensitivity reactions. In clinical trials, infusion-related
reactions
occurred in approximately 1 to 7% of patients treated
with ULTOMIRIS. These events included lower back pain, drop 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.
ADVERSE REACTIONS
Adverse reactions reported in ≥10% or more of patients with PNH
were upper respiratory tract infection and headache. Serious
adverse reactions were reported in 15 (6.8%) patients receiving
ULTOMIRIS. The serious adverse reactions in patients treated
with ULTOMIRIS included
hyperthermia and
pyrexia. No serious adverse reaction was reported in
more than 1 patient treated with ULTOMIRIS. One fatal case of
sepsis was identified in a patient treated with ULTOMIRIS. In clinical
studies, clinically relevant adverse reactions in 1% of adult patients
include infusion-related reactions.
Adverse reactions reported in ≥10% of pediatric patients treated with ULTOMIRIS who were treatment-naïve vs. Eculizumab-experienced were anemia (20% vs. 25%), abdominal pain (0% vs. 38%), constipation (0% vs. 25%), pyrexia (20% vs. 13%), upper respiratory tract infection (20% vs. 75%), pain in extremity (0% vs. 25%), and headache (20% vs. 25%).
DRUG INTERACTIONS
Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins
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.
Neonatal Fc Receptor Blockers
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.
INDICATION
ULTOMIRIS is indicated for the treatment of adult and pediatric patients one month of age and older with paroxysmal nocturnal hemoglobinuria (PNH).
To report SUSPECTED ADVERSE REACTIONS, contact Alexion
Pharmaceuticals, Inc. at
1-844-259-6783 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information for ULTOMIRIS, including Boxed WARNING regarding serious and life-threatening or fatal meningococcal infections.
