Seizures: In Study 1, seizures occurred in 1% of ZINBRY TA-treated patients, compared with 0.3% of
AVONEX-treated patients. In Study 2, no seizures occurred in either treatment group.
Immune-Mediated Disorders: Types of immune-mediated or autoimmune conditions that
were observed in 2 or more ZINBRYTA-treated patients include type I diabetes, celiac disease,
autoimmune thyroiditis, immune hemolytic anemia, thrombocytopenia, pancreatitis,
glomerulonephritis, sarcoidosis, rheumatoid arthritis, thyroiditis, and sialadenitis [see Warnings and
Precautions ( 5. 2)]. The relationship of these events to ZINBRY TA is unknown.
Breast Cancer: In controlled studies, 1 ZINBRY TA-treated woman developed breast cancer
compared with none in the AVONEX-treated group. Across all controlled and open-label clinical
studies, 8 of 1485 (0.5%) ZINBRY TA-treated women developed breast cancer, and 1 of 751 (0.1%)
ZINBRY TA-treated men developed breast cancer. It is unclear whether this represents an incidence
increase over background rate.
6. 2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. In Study 1, patients were
tested for anti-drug (daclizumab) antibodies at Week 4 and approximately every 3 months
thereafter. Anti-drug antibodies and neutralizing antibodies were observed in 19% (175/913)
and 8% (71/913) of patients, respectively. Anti-drug antibody responses were transient in 12%
(110/913) of patients and persistent in 7% (65/913) of patients. Anti-drug and neutralizing antibody
responses predominantly occurred during the first year of treatment, and their frequency declined
with continued ZINBR Y TA treatment.
In patients with neutralizing antibodies, daclizumab clearance was increased on average by
19% [see Clinical Pharmacology ( 12. 3)]. There was no apparent correlation of anti-drug antibody or
neutralizing antibody development to clinical response, adverse reactions, or pharmacodynamic
profile of ZINBRY TA.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the
assay. Additionally, the observed incidence of 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 daclizumab with the incidence of antibodies to other products may
7 DRUG IN TERAC TIONS
7. 1 Hepatotoxic Drugs
Caution should be used when using hepatotoxic drugs, including non-prescription products,
concomitantly with ZINBRYTA. Carefully consider the need for the use of herbal products or
dietary supplements that can cause hepatotoxicity [see Warnings and Precautions ( 5. 1)].
8 USE IN SPECIFIC POPULATIONS
8. 1 Pregnancy
Risk Summary: There are no adequate data on the developmental risk associated with use of
ZINBRY TA in pregnant women. Administration of ZINBRY TA to monkeys during gestation resulted
in embryofetal death and reduced fetal growth at maternal exposures greater than 30 times
that expected clinically [see Data]. In the U. S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-
20%, respectively. The background risk of major birth defects and miscarriage for the indicated
population is unknown.
Animal Data: In monkeys administered ZINBRY TA (0, 10, 50, or 200 mg/kg) weekly by subcutaneous
injection during organogenesis (gestation days 20 through 50), there was a decrease in fetal body
weight and crown-rump length, and an increase in embryofetal death at the highest dose tested.
Plasma exposure (AUC) at the no-effect dose of 50 mg/kg was approximately 30 times that in
humans at the recommended human dose (RHD) of 150 mg. In monkeys administered ZINBRY TA
(50 mg/kg) weekly by subcutaneous injection from gestation day 50 to birth, there were no effects
on pre- or postnatal development for up to 6 months after birth. Plasma exposure (AUC) at the
administered dose was 55 times that in humans at the RHD.
8. 2 Lactation
Risk Summary: There are no data on the presence of daclizumab in human milk, the effects on the
breastfed child, or the effects of the drug on milk production. Daclizumab was excreted in the milk
of ZINBRY TA-treated monkeys. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for ZINBRY TA and any potential adverse effects on
the breastfed child from ZINBRY TA or from the underlying maternal condition.
8. 4 Pediatric Use
Safety and effectiveness of ZINBRY TA in patients less than 17 years old have not been established.
Use of ZINBRY TA is not recommended in pediatric patients due to the risks of hepatic injury and
immune-mediated disorders [see Warnings and Precautions ( 5. 1, 5. 2)].
8. 5 Geriatric Use
Clinical studies of ZINBRY TA did not include a sufficient number of patients aged 65 and over to
determine whether they respond differently than younger patients.
8. 6 Hepatic Impairment
Clinical trials did not include patients with ALT or AS T more than two times the ULN. Patients
with signs and symptoms of hepatic impairment may be at increased risk for hepatotoxicity
from ZINBRY TA [see Dosage and Administration ( 2. 3, 2. 4), Contraindications ( 4), and Warnings and
Precautions ( 5. 1)].
17 PATIEN T COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide and
Instructions for Use).
Hepatic Injury: Inform the patient of the risk of severe hepatic injury associated with ZINBRY TA.
Advise patients of the symptoms of hepatic dysfunction, and instruct patients to report such
symptoms to their healthcare provider immediately [see Warnings and Precautions ( 5. 1)].
Discuss with the patient the importance of measuring hepatic laboratory values and having them
evaluated by the healthcare provider monthly while taking ZINBRY TA and for up to 6 months after
the last dose of ZINBRY TA.
Discuss with the patient the risk of concomitant use of other hepatotoxic medications, over the
counter medications, herbal products, or dietary supplements.
Inform the patient that they will be given a ZINBRY TA Patient Wallet 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.
Advise the patient to show the ZINBRY TA Patient Wallet Card to other treating healthcare providers.
Immune-Mediated Disorders: Advise patients that ZINBRY TA can cause their immune system to
attack healthy cells in their body and that this can affect any organ system.
Skin Reactions: Advise patients that ZINBRY TA can cause dermatologic reactions that can range
from mild rashes to serious reactions that could require treatment with other medications or
result in hospitalization. Instruct patients to seek immediate medical attention if dermatologic
reactions occur [see Warnings and Precautions ( 5. 2)].
Lymphadenopathy: Inform patients that ZINBRY TA may cause lymphadenopathy that can range
from mild events that can resolve on their own to serious lymphadenopathy that may require
invasive procedures for diagnosis. Inform patients of the symptoms and instruct patients
to contact their healthcare provider if they develop lymphadenopathy [see Warnings and
Precautions ( 5. 2)].
Non-Infectious Colitis: Inform patients that ZINBRY TA may cause gastrointestinal reactions
that may be serious and could require treatment. Advise patients of the symptoms of colitis
and instruct patients to promptly contact their healthcare provider if they experience these
symptoms [see Warnings and Precautions ( 5. 2)].
ZINBRY TA REMS Program
ZINBR Y TA is available only through a restricted program called the ZINBRY TA REMS Program
[see Warnings and Precautions ( 5. 3)]. Inform the patient of the following notable requirements:
• Patients must enroll in the program and comply with ongoing monitoring
requirements [see Warnings and Precautions ( 5. 1, 5. 2)].
ZINBR Y TA is available only from certified pharmacies participating in the program. Therefore,
provide patients with the telephone number and website for information on how to obtain
Allergic Reactions and Anaphylaxis: Advise patients of the symptoms of allergic reactions and
anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur
[see Warnings and Precautions ( 5. 4)].
Risk of Infections: Inform patients that they may be more likely to get infections when taking
ZINBR Y TA, and that they should contact their healthcare provider if they develop symptoms of
infection [see Warnings and Precautions ( 5. 5)].
Depression and Suicide: Advise patients of the symptoms of depression and suicidal ideation
as they have occurred with the use of ZINBRY TA and instruct patients to report symptoms of
depression or thoughts of suicide to their healthcare provider immediately [see Warnings and
Precautions ( 5. 6)].
Instructions for Self-Injection Technique and Procedures: Provide appropriate instruction for
methods of self-injection, including careful review of the ZINBR Y TA Instructions for Use. Instruct
the patient in the use of aseptic technique when administering ZINBRY TA. Inform the patient
that a healthcare provider should show them or their caregiver how to inject ZINBRY TA before
administering the first dose. Tell the patient not to re-use needles or syringes, and instruct the
patient on safe disposal procedures. Inform the patient to dispose of used needles and syringes
in a puncture-resistant container.
Adverse Reaction ZINBR Y TA
150 mg SQ
Every 4 Weeks
N = 208
N = 204
tract infection 9 7
Depression1 7 2
Rash2 7 3
Pharyngitis 6 4
Increased ALT 5 2
Rhinitis 4 1
Anemia 3 < 1
Pyrexia 3 < 1
Increased AST 3 < 1
Dermatitis3 3 < 1
Table 3: Adverse Reactions in Adults with RMS with an Incidence at Least 2% More
for ZINBRY TA 150 mg SQ Every 4 Weeks than Placebo (Study 2)
1 includes depressed mood and depression
2 includes erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash,
pruritic rash, rash, and vesicular rash
3 includes allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis,
and seborrheic dermatitis
Other clinically relevant adverse reactions observed at <2% difference included abnormal liver
function test, decreased lymphocyte count, diarrhea, dry skin, erythema, folliculitis, increased
hepatic enzyme, laryngitis, lymphadenitis, pneumonia, pruritus, psoriasis, respiratory tract
infection, skin exfoliation, toxic skin eruption, and viral infection.
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ZINBRYTA is a trademark of Biogen.
© 2016 Biogen and AbbVie Inc. 05/2016 ZIN-US-0473