Additions and/or
revisions underlined:
ZINBRYTA can cause severe liver injury, including autoimmune hepatitis and
liver failure. Fatal cases have
occurred. Liver injury, including autoimmune hepatitis and acute liver
failure, can occur at any time during treatment with ZINBRYTA, with cases
reported up to 5 months after the last dose of ZINBRYTA.
In addition to autoimmune hepatitis, a variety of immune-mediated
disorders including skin reactions, lymphadenopathy, non-infectious
colitis, and other serious conditions can occur in patients treated with
ZINBRYTA. Overall, serious
immune-mediated disorders were observed in 5% of patients treated with
ZINBRYTA.
Additions and/or revisions underlined:
5.1 Hepatic Injury
ZINBRYTA can cause
severe liver injury, including autoimmune hepatitis and liver failure. Fatal
cases have occurred. In controlled
studies …
… Across all
clinical studies (controlled and open-label), 0.3% of ZINBRYTA-treated patients
were diagnosed with autoimmune hepatitis. One fatal case of autoimmune
hepatitis with acute liver failure occurred in a patient re-initiating
ZINBRYTA after a planned 6 month … upper limit of normal (ULN).
Addition of the following:
Another case of
acute liver failure occurred in a patient receiving ZINBRYTA in the
postmarketing setting after 4 doses of ZINBRYTA, resulting in transplant and
death. This patient had normal serum transaminase and total bilirubin levels 6
days prior to the last administration of ZINBRYTA. The patient was also
receiving concomitant treatment with another drug known to be associated with
hepatic injury.
Monitoring
Early
identification of elevated liver enzymes may decrease the risk of a serious
outcome.
Prior to starting treatment … based on serum
transaminase and total
bilirubin values.
Liver failure can
occur at any time during treatment with ZINBRYTA even with monthly liver enzyme
monitoring indicating normal values prior to each dose. Liver injury has been
reported up to 5 months after the last dose of ZINBRYTA. Some cases of liver
injury may be associated with fever, skin rash, or other immune-mediated
disorders.
Monitor patients
for signs and symptoms of hepatic injury. If a patient develops clinical
signs …
5.2 Immune-Mediated Disorders
Skin Reactions
Additions and/or revisions underlined:
… In patients with
a history of skin conditions, including eczema or psoriasis, use of ZINBRYTA
may exacerbate those conditions. In addition to serious cases of dermatitis,
eczema, psoriasis and drug eruptions, cases of erythema multiforme, erythema
nodosum, exfoliative rash, and oral ulcers occurred in ZINBRYTA clinical
trials. Treatment of skin reactions included treatment with topical or
systemic corticosteroids or immunosuppressant drugs, including
tacrolimus.
Addition of the following subsection:
Autoimmune
Hemolytic Anemia
Across all
clinical studies (controlled and open-label), autoimmune hemolytic anemia
occurred in less than 1% of patients treated with ZINBRYTA. Autoimmune hemolytic anemia resolved with
discontinuation of ZINBRYTA, corticosteroid or other immunosuppressant
treatment, and blood transfusions in most cases. If a patient develops signs or symptoms of
autoimmune hemolytic anemia (e.g., pallor, fatigue, dark urine, jaundice,
shortness of breath), consider discontinuing ZINBRYTA and referring to an
appropriate specialist for further evaluation and treatment.
Immune-mediated
Colitis
Additions and/or revisions underlined:
An increased
incidence of serious colitis (less than 1%) was reported in patients treated
with ZINBRYTA compared with none for patients treated with AVONEX or placebo in
clinical trials. Cases have included reports of colitis, ulcerative colitis,
Crohn’s disease, microscopic colitis, inflammatory bowel disease, proctitis,
and proctocolitis. Consider discontinuing ZINBRYTA and referring patients
who develop symptoms of colitis (e.g., abdominal pain, fever, prolonged
diarrhea, bloody stools) to a specialist.
Other
Immune-mediated Disorders
A wide variety of
other immune-mediated disorders, some serious, have occurred with the use of
ZINBRYTA. These include single organ or systemic multi-organ inflammatory
reactions. Some required treatment with systemic corticosteroids or other
immunosuppressants. Some required several months for resolution after the
last dose of ZINBRYTA, and some had not resolved even several months after
discontinuation of ZINBRYTA, at the time of last reported follow-up.
5.5 Infections
Addition of the following:
Cytomegalovirus
(CMV) infections (hepatitis and pneumonia) occurred in ZINBRYTA-treated
patients in clinical trials.
Following Table 3 Adverse Reactions in Adults with RMS
with an Incidence at Least 2% More for Zinbryta 150mg SQ Every 4 Weeks than
Placebo (Study 2); additions and/or revisions underlined:
Other clinically relevant adverse reactions observed at less
than 2% difference from AVONEX or placebo in controlled trials included
abnormal liver function test, colitis, decreased lymphocyte count, diarrhea,
dry
skin, erythema,
folliculitis, increased
hepatic enzyme, laryngitis, lymphadenopathy, pneumonia,
pruritus,
psoriasis, respiratory tract infection,
skin exfoliation, toxic skin eruption,
vasculitis, and viral infection.
Immune-mediated Disorders
In addition to immune-mediated
hepatitis, skin reactions, colitis, lymphadenopathy, and autoimmune hemolytic
anemia, types of immune-mediated or autoimmune conditions that were
observed in 2 or more ZINBRYTA-treated patients in controlled and open-label
trials include immune cytopenias (agranulocytosis, thrombocytopenia, and
pancytopenia), type I diabetes, celiac disease, immune-mediated
thyroiditis , interstitial lung disease, lupus-like syndrome, pancreatitis,
glomerulonephritis, rheumatoid arthritis, sarcoidosis, seronegative
arthritis, sialadenitis, vasculitis, vitiligo, and multiorgan
hypersensitivity.
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