were observed in 4% of patients treated with ZINBRY TA compared with less than 1% for AVONEX-treated patients. In the placebo-control study (Study 2), immune-mediated disorders were
observed in 13% of ZINBR Y TA-treated patients compared with 7% of placebo-treated patients. In
Study 2, serious immune-mediated disorders were observed in 0.5% of ZINBRY TA-treated patients
and in 0.5% of placebo-treated patients. In some cases, patients had concurrent or sequential
occurring disorders while taking ZINBRY TA.
Some patients required invasive procedures for diagnosis (e.g., colonoscopy, liver biopsy, kidney
biopsy, lung biopsy), hospitalization for fluid replacement or blood transfusion, or prolonged
treatment with systemic corticosteroids or immunosuppressant drugs. Some of these events did
not resolve after stopping ZINBRY TA during study follow-up.
Prescribers should be vigilant regarding emergent immune-mediated disorders. For suspected
immune-mediated disorders, ensure adequate evaluation to confirm etiology or to exclude other
causes. If a patient develops a serious immune-mediated disorder, consider stopping ZINBR Y TA
and refer the patient to an appropriate specialist for further evaluation and treatment.
Skin Reactions: ZINBRY TA causes skin reactions. In clinical trials, skin reactions occurred in 37%
of ZINBRY TA-treated patients compared with 19% of AVONEX-treated patients (Study 1) and in
18% of ZINBRY TA-treated patients compared with 13% of patients on placebo (Study 2). Skin
reactions occurred at any time during treatment with ZINBRY TA. Rashes occurred in 11% of
ZINBRY TA-treated patients compared to 4% of AVONEX-treated patients, and in 7% of ZINBR Y TA-treated patients compared to 3% of patients on placebo. Dermatitis occurred more frequently
in ZINBRY TA-treated patients compared to AVONEX-treated patients or to patients on placebo,
and eczema was observed more frequently in ZINBRY TA-treated patients compared to AVONEX-treated patients [see Adverse Reactions ( 6. 1)]. Psoriatic conditions occurred in 2% of ZINBRY TA-treated patients compared with 0.3% of AVONEX-treated patients. Photosensitivity also occurred.
Serious skin reactions occurred in 2% of patients treated with ZINBR Y TA compared with 0.1%
of patients on AVONEX (Study 1) and in 1% of patients treated with ZINBR Y TA compared with
none treated with placebo (Study 2). One death resulted from infectious complications following
a serious cutaneous reaction. In patients with a history of skin conditions, including eczema
or psoriasis, use of ZINBRY TA may exacerbate those conditions. Treatment of skin reactions
included treatment with topical or systemic steroids or immunosuppressant drugs, including
tacrolimus. In clinical trials, discontinuation because of skin reactions was 4% in ZINBRY TA-treated
patients. Rashes took a mean of 3 months to resolve; some were unresolved at the time of the
last evaluation. If a patient develops a serious diffuse or inflammatory rash, it is recommended
that a dermatologist evaluate the patient before the next dose of ZINBRY TA. Discontinuation of
ZINBRY TA may be appropriate.
Lymphadenopathy: ZINBRY TA increases the incidence of lymphadenopathy. In controlled studies,
lymphadenopathy or lymphadenitis occurred in 6% of ZINBRY TA-treated patients compared with
1% of AVONEX-treated patients (Study 1) and in 2% of ZINBRY TA-treated patients compared with
1% of placebo-treated patients (Study 2). Onset of lymphadenopathy or lymphadenitis occurred
throughout the treatment period. Serious events related to lymphadenopathy or lymphadenitis
included infections, benign salivary neoplasm, skin reactions, thrombocytopenia, and interstitial
lung changes [see Warnings and Precautions ( 5. 5)]. The majority of cases resolved with or without
continued treatment with ZINBRY TA and took a mean of 3 months to resolve. Lymphadenopathy
resulted in discontinuation in 0.6% of ZINBRY TA-treated patients.
Some patients with lymphadenopathy under went diagnostic biopsy. In the event that lymph
node biopsy is considered, full diagnostic evaluation should be conducted by a specialist.
Non-Infectious Colitis: An increased incidence of serious colitis (less than 1%) was reported in
patients treated with ZINBRY TA compared with none for patients treated with AVONEX or placebo
in clinical trials. Consider referring patients who develop symptoms of colitis (e.g., abdominal pain,
fever, prolonged diarrhea) to a specialist.
Other Immune-Mediated Disorders: A wide variety of other immune-mediated disorders, some
serious, have occurred infrequently with the use of ZINBRY TA. These include single organ or systemic
multi-organ inflammatory reactions. Many events occurred in only one patient, and the relationship
to ZINBRY TA is unknown [see Adverse Reactions ( 6. 1)]. Some required treatment with systemic
corticosteroids. Some required several months for resolution after the last dose of ZINBRY TA.
For suspected immune-mediated disorders, ensure adequate evaluation to confirm etiology or to
exclude other causes. If a patient develops a serious immune-mediated disorder, consider stopping
ZINBRY TA and refer the patient to an appropriate specialist for further evaluation and treatment.
5. 3 ZINBRY TA REMS Program
ZINBRY TA is available only through a restricted program under a Risk Evaluation and Mitigation
Strategy (REMS) called the ZINBRY TA REMS Program, because of the risks of hepatic injury including
autoimmune hepatitis, and other immune-mediated disorders [see Warnings and Precautions ( 5. 1, 5. 2)].
Notable requirements of the ZINBRY TA REMS Program include the following:
• Prescribers must be certified with the program by enrolling and completing training.
• Patients must enroll in the program and comply with ongoing monitoring requirements
[see Warnings and Precautions ( 5. 1, 5. 2)].
• Pharmacies must be certified with the program and must only dispense to patients who are
authorized to receive ZINBR Y TA.
Further information, including a list of qualified pharmacies/distributors, is available at 1-800-456-2255
5. 4 Acute Hypersensitivity
ZINBRY TA can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time
during treatment. Discontinue and do not restart ZINBRY TA if anaphylaxis or other allergic
reactions occur [see Contraindications ( 4)].
5. 5 Infections
ZINBRY TA increases the risk for infections. In controlled trials, infections occurred in 65% of
ZINBRY TA-treated patients compared with 57% of AVONEX-treated patients (Study 1) and in 50%
of ZINBRY TA-treated patients compared with 44% of patients taking placebo (Study 2). Serious
infections occurred in 4% of ZINBRY TA-treated patients compared with 2% of AVONEX-treated
patients (Study 1) and in 3% of ZINBRY TA-treated patients compared with none on placebo (Study 2).
The most common types of infections observed were upper respiratory tract infections, urinary
tract infections and viral infections.
In clinical trials, cases of tuberculosis occurred in countries where tuberculosis is endemic. Evaluate
high-risk patients for tuberculosis infection prior to initiating treatment with ZINBRY TA.
For patients testing positive for tuberculosis, treat by standard medical practice prior to therapy
with ZINBRY TA [see Dosage and Administration ( 2. 3)].
Avoid initiating ZINBRY TA in patients with severe active infection until the infection is fully controlled. If
serious infection develops, consider withholding treatment with ZINBRY TA until the infection resolves.
Vaccination: The safety of immunization with live viral vaccines during treatment with ZINBRY TA
has not been studied. Vaccination with live vaccines is not recommended during treatment and
up to 4 months after discontinuation of ZINBRY TA [see Dosage and Administration ( 2. 3)].
5. 6 Depression and Suicide
Depression-related events occurred more frequently in patients receiving ZINBRY TA than in patients
receiving AVONEX or placebo. In controlled trials, depression-related events occurred in 10% of
ZINBRY TA-treated patients compared with 8% of AVONEX-treated patients (Study 1) and in 7%
of ZINBRY TA-treated patients compared with 2% of patients taking placebo (Study 2). In Study 1,
serious events related to depression, including suicidal ideation or suicide attempt, occurred in 0.4%
of ZINBRY TA-treated patients and in 0.7% of AVONEX-treated patients. None occurred in Study 2
Administer ZINBR Y TA with caution to patients with previous or current depressive disorders.
Advise patients and/or caregivers to immediately report any symptoms of new or worsening
depression and/or suicidal ideation to their healthcare provider.
If a patient develops severe depression and/or suicidal ideation, consider discontinuation of ZINBRY TA.
6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in labeling:
• Hepatic Injury [see Warnings and Precautions ( 5. 1)]
• Immune-Mediated Disorders [see Warnings and Precautions ( 5. 2)]
• Acute Hypersensitivity [see Warnings and Precautions ( 5. 4)]
• Infections [see Warnings and Precautions ( 5. 5)]
• Depression and Suicide [see Warnings and Precautions ( 5. 6)]
6. 1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of ZINBRY TA cannot be directly compared with rates in clinical trials of
other drugs and may not reflect the rates observed in practice.
In all controlled and uncontrolled trials performed in patients with relapsing multiple sclerosis, 2236
patients received ZINBRY TA for a total of 5214 person-years. Of these patients, 1576 received ZINBRY TA
for at least 1 year, 1259 for at least 2 years, and 888 for at least 3 years. In the controlled studies,
approximately 67% were female, 92% were Caucasian, and the mean age was 36 years at study entry.
In the active-controlled study (Study 1), 919 patients received ZINBRY TA (150 mg SQ, every 4 weeks)
and 922 patients received AVONEX (interferon beta-1a 30 mcg IM, weekly) for a minimum of 2 years
and up to 3 years, with 1952 person-years of exposure to ZINBRY TA; the median length of treatment
was approximately 27 months. The adverse reactions from Study 1 are presented in Table 2.
In the placebo-controlled study (Study 2), 417 patients received ZINBRY TA with 423 person-years of
exposure, of which 208 received 150 mg, and 204 received placebo every 4 weeks for up to 1 year;
the median length of treatment was approximately 11 months. The adverse reactions from Study 2
are presented in Table 3.
The most common adverse reactions (incidence at least 5% and at least 2% higher incidence
than comparator) that occurred in ZINBR Y TA-treated patients were nasopharyngitis, upper
respiratory tract infection, rash, influenza, dermatitis, oropharyngeal pain, bronchitis, eczema, and
lymphadenopathy compared with AVONEX; and upper respiratory tract infection, depression,
rash, pharyngitis, and increased alanine aminotransferase (ALT) compared with placebo.
The most common adverse reactions leading to discontinuation in up to 5% of patients treated with
ZINBRY TA were hepatic events including elevations of serum transaminases and cutaneous events.
Patients were excluded from the clinical studies for abnormal laboratory values including
hemoglobin, complete blood count with differential, serum transaminases, or serum creatinine.
Patients were excluded if they had a history of seizure disorder or of having a seizure within 6
months of beginning the study, or suicidal ideation or severe depression within 3 months of
beginning the study. During Study 1, concomitant use of ZINBRY TA with the hepatotoxic drugs
valproic acid, carbamazepine, lamotrigine, phenytoin, isoniazid, and propylthiouracil was not
permitted except in patients already receiving the drugs at the time of study entry.
In clinical studies, serum chemistry was evaluated at baseline and monthly. Hematology was
evaluated at baseline, monthly for 6 months, and then every 3 months. Thyroid function was
measured at baseline and every 6 months.
1 includes upper respiratory tract infection and viral upper respiratory tract infection
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
4 includes dyshidrotic eczema, eczema, and nummular eczema
Adverse Reaction ZINBR Y TA
150 mg SQ
Every 4 Weeks
N = 919
30 mcg IM
N = 922
Nasopharyngitis 25 21
tract infection1 17 14
Rash2 11 4
Influenza 9 6
Dermatitis3 9 2
Oropharyngeal pain 8 4
Bronchitis 7 5
Eczema4 5 2
Lymphadenopathy 5 < 1
Tonsillitis 4 2
Acne 3 < 1
Table 2: Adverse Reactions in Adults with RMS with an Incidence at Least 2% More for
ZINBRY TA 150 mg SQ Every 4 Weeks than AVONEX 30 mcg IM Once Weekly (Study 1)