Approved Drug Label (PDF)
5
Warnings and Precautions
5.6 Hypersensitivity Reactions, Including Anaphylaxis
Additions and/or revisions underlined:
…
In the postmarketing setting, events of hypersensitivity reactions,
including anaphylaxis and death have occurred in patients treated with a range
of doses of intravenous tocilizumab products, with or without concomitant
therapies. Events have occurred in patients who received premedication.
Hypersensitivity, including anaphylaxis events, have occurred both with and
without previous hypersensitivity reactions and as early as the first infusion
of tocilizumab products. In addition, serious cutaneous reactions,
including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have
been reported in patients with autoinflammatory conditions treated with
tocilizumab products.
TOFIDENCE for intravenous use should only be infused by a healthcare
professional with appropriate medical support to manage anaphylaxis. If a
hypersensitivity reaction occurs immediately discontinue TOFIDENCE; treat
promptly and monitor until signs and symptoms resolve.
6
Adverse Reactions
6.6 Postmarketing Experience
Additions and/or revisions underlined:
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Inform
patients that some patients who have been treated with TOFIDENCE have developed
serious allergic reactions, including anaphylaxis and serious skin reactions
[see Warnings and Precautions (5.6)]. Advise
patients to stop taking TOFIDENCE and seek immediate medical
attention if they experience any symptom of serious allergic reactions (including
rash, hives, and swelling of the face, lips, tongue, and throat that may cause
difficulty in breathing or swallowing).
…
MEDICATION GUIDE
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and/or revisions underlined:
…
What
are the possible side effects with TOFIDENCE? TOFIDENCE can cause serious side
effects, including:
…
Serious Allergic
Reactions. Serious
allergic reactions, including death, can happen with TOFIDENCE. These reactions
can happen with any infusion of TOFIDENCE, even if they did not occur with an
earlier infusion. Stop taking TOFIDENCE, contact healthcare provider, and
get emergency help right away if you have any of the following signs of a
serious allergic reaction:
trouble
breathing
swelling
of your mouth, lips, tongue, or face
wheezing
severe
itching
skin rash, hives, redness, or swelling outside of the
injection site area
dizziness or fainting
fast heartbeat or pounding in your chest
(tachycardia),
sweating
…
Tell
your healthcare provider about any side effect that bothers you or does not go
away. These are not all the possible side effects of TOFIDENCE. For more information,
ask your healthcare provider or pharmacist.
…
Approved Drug Label (PDF)
Boxed Warning
Additions and revisions underlined:
. . .
If a serious infection develops,
interrupt TOFIDENCE until the infection
is controlled. Reported
infections include:
Patients, except those with COVID-19, should be tested for latent
tuberculosis before TOFIDENCE
use and during therapy.
. . .
5
Warnings and Precautions
5.1 Serious Infections
Additions and revisions underlined:
. . .
COVID-19
In patients with COVID-19, monitor
for signs and symptoms of new infections during
and after treatment with
TOFIDENCE. There is limited information regarding the use of tocilizumab
products in patients with COVID-19 and concomitant active serious infections.
The risks and benefits of treatment
with TOFIDENCE in COVID-19 patients
with other concurrent infections should be considered.
Tuberculosis
Evaluate patients for tuberculosis risk factors and test for
latent infection prior to initiating TOFIDENCE. In patients with COVID-19, testing
for latent infection is not necessary prior to initiating
treatment with TOFIDENCE.
. . .
5.3 Hepatotoxicity
Additions and revisions underlined:
. . .
For RA and GCA patients,
obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate
aminotransferase [AST], alkaline phosphatase, and total bilirubin) before
initiating TOFIDENCE, every 4 to 8 weeks after start of therapy for the first 6
months of treatment and every 3 months thereafter. It is not recommended to
initiate TOFIDENCE treatment in RA or GCA
patients with elevated
transaminases ALT or AST greater
than 1.5x ULN.
. . .
Patients hospitalized with COVID-19 may have elevated
ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision
to administer TOFIDENCE should balance the potential benefit of treating
COVID-19 against the potential risks of acute treatment with TOFIDENCE. It is
not recommended to initiate TOFIDENCE treatment in COVID-19 patients with
elevated ALT or AST above 10 x ULN. Monitor ALT and AST during treatment.
5.4 Changes in Laboratory Parameters
Patients with Rheumatoid Arthritis, Giant Cell Arteritis
and Coronavirus Disease
2019
Subsection title revised
Additions and revisions underlined:
. . .
It is not recommended to initiate TOFIDENCE treatment in RA and
GCA patients with a low neutrophil count,
i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an absolute neutrophil count
less than 500 per mm3 treatment is not recommended.
Monitor neutrophils 4 to 8 weeks after
start of therapy
and every 3 months thereafter [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results
see Dosage and Administration
(2.8).
It is not recommended to initiate TOFIDENCE treatment in COVID-19
patients with an ANC
less than 1000 per mm3 . Neutrophils should be monitored.
Thrombocytopenia
Treatment with tocilizumab products was associated
with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding
events in clinical trials [see Adverse Reactions (6.1)].
- It is not recommended to initiate
TOFIDENCE treatment in RA and GCA patients with a platelet count
below 100,000 per mm3. In patients who develop a platelet count
less than 50,000 per mm3 treatment is
not recommended.
In COVID-19 patients
with a platelet count less than 50,000
per mm3 , treatment is not
recommended. Platelets should be monitored.
6
Adverse Reactions
6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)
Additions and revisions underlined:
Immunogenicity
The observed incidence of anti-drug antibodies is
highly dependent on the sensitivity and specificity of the assay. Differences
in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies
described below with the incidence
of anti-drug antibodies
in other studies, including those of tocilizumab or of other
tocilizumab products.
6.2 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)
Newly added subsection:
The safety of tocilizumab-IV was studied in an open label PK-PD and safety
study in 24 patients
with GCA who were in remission on tocilizumab-IV at time of enrollment.
Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6
mg/kg every 4 weeks for 20 weeks. The total patient years exposure to treatment
was 17.5 years.
The safety of tocilizumab by another route of
administration has been studied in one Phase III study with 251 GCA patients. The total patient
years duration was 138.5 patient
years during the 12-month double blind,
placebo-controlled phase of the study. The overall safety profile observed was
generally consistent with the known safety profile of tocilizumab. There was an
overall higher incidence of infections in GCA patients relative to RA patients.
The overall safety profile observed
for tocilizumab administered intravenously in GCA patients
was consistent with the known safety profile of tocilizumab.
6.5 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV)
Newly added subsection, please refer to label
7
Drug Interactions
7.1 Concomitant Drugs for Treatment of Adult Indications
Additions and revisions underlined:
In RA patients,
population pharmacokinetic analyses
did not detect any effect of methotrexate (MTX), non-steroidal
anti-inflammatory drugs or corticosteroids on tocilizumab clearance.
Concomitant administration of a single
intravenous dose of 10 mg/kg
tocilizumab with 10-25
mg MTX once weekly had no clinically significant effect on MTX exposure.
Tocilizumab products have not been studied in combination with biological
DMARDs such as TNF antagonists [see
Dosage and Administration (2.2)].
In GCA
patients, no effect of concomitant corticosteroid on tocilizumab exposure
was observed.
8
Use in Specific Populations
8.4 Geriatric Use
Additions and revisions underlined:
Of the 2644 patients who received tocilizumab in
Studies I to V [see Clinical Studies
(14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. The frequency of
serious infection among tocilizumab treated subjects 65 years of age and older
was higher than those under the age of 65. As there is a higher incidence of
infections in the elderly population in general, caution should be used when
treating the elderly.
In the EMPACTA,
COVACTA, and REMDACTA
studies, of the 974 COVID-19
patients in the tocilizumab arm, 375 (39%) were 65
years of age or older. No overall differences in safety or effectiveness of tocilizumab were observed between
patients 65 years
of age and older and those
under the age of 65 years of age in these studies [see Adverse Reactions (6.5) and Clinical Studies (14.5)].
In the RECOVERY study, of the 2022 COVID-19
patients in the tocilizumab arm, 930 (46%) were 65 years of age or older. No
overall differences in effectiveness of tocilizumab were observed between
patients 65 years of age and older and those
under the age 65 years
of age in this study [see
Clinical Studies (14.5)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
Additions and revisions underlined:
TOFIDENCE can
cause serious side effects including:
Serious Infections. TOFIDENCE is a medicine that affects your immune
system. TOFIDENCE can lower the ability of your immune system
to fight infections. Some people have serious infections while taking TOFIDENCE, including tuberculosis (TB),
and infections caused by bacteria, fungi, or viruses that can spread throughout
the body. Some people have died from these infections. Your healthcare provider
should assess you for TB before starting TOFIDENCE (except if you have
COVID-19).
If you have COVID-19, your healthcare provider
should monitor you for signs
and symptoms of new infections during and after treatment with TOFIDENCE.
. . .
Your healthcare provider
should do blood
tests before you start
receiving TOFIDENCE. If you have rheumatoid arthritis (RA) or giant cell
arteritis (GCA) your healthcare provider should do blood tests
every 4 to 8 weeks
after you start receiving TOFIDENCE for the first 6 months and then every 3 months after
that.
. . .
What is TOFIDENCE?
TOFIDENCE is a prescription medicine
called an Interleukin-6 (IL-6) receptor antagonist. TOFIDENCE is used:
To treat adults
with moderately to severely active
rheumatoid arthritis (RA),
after at least
one other medicine called a Disease-Modifying
Anti-Rheumatic Drug (DMARD) has been used and did not work well.
To treat adults
with giant cell arteritis (GCA).
To treat people with active PJIA ages 2 and above.
To treat people with active SJIA ages 2 and above.
To treat hospitalized adults with coronavirus disease 2019 (COVID-19) receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation.
. . .
How will I receive
TOFIDENCE?
Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA, SJIA, or COVID-19:
If your healthcare provider prescribes TOFIDENCE as an IV infusion, you
will receive TOFIDENCE from a healthcare provider through
a needle placed in a vein in your arm. The infusion
will take about 1 hour to give you
the full dose of medicine.
For rheumatoid arthritis, giant cell arteritis
or PJIA you will receive
a dose of TOFIDENCE about every 4 weeks.
For SJIA you will receive
a dose of TOFIDENCE about every 2 weeks.
For COVID-19, you will receive
a single dose of TOFIDENCE, and if needed
one additional dose.
While taking TOFIDENCE, you may continue to use other medicines that
help treat your rheumatoid arthritis, PJIA, SJIA, or COVID-19 such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription
steroids, as instructed by your healthcare provider.
. . .
You may also report side effects to Biogen MA Inc. at 1-877-422-8360.