HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` ZINBRYTA™ safely and effectively. See full prescribing information for
`
`
`
`
` ZINBRYTA.
`
` ZINBRYTA (daclizumab) injection, for subcutaneous use
`
`
` Initial U.S. Approval: 2016
`
`
`
`
`
`
`WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE
`
`
`
`
`HEPATITIS and OTHER IMMUNE-MEDIATED DISORDERS
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`
`
`Hepatic Injury Including Autoimmune Hepatitis
`
`
`
`  ZINBRYTA can cause severe liver injury including life-threatening
`
`
`events, liver failure, and autoimmune hepatitis. Obtain transaminase
`
`
`and bilirubin levels before initiation of ZINBRYTA. Monitor and
`
`evaluate transaminase and bilirubin levels monthly and up to 6 months
`
`
`
`
`
`after the last dose (2 3, 2.4, 5 1).
`
`
`  ZINBRYTA is contraindicated in patients with pre-existing hepatic
`
`
`disease or hepatic impairment (4, 5.1).
`
`
`
`
`
`
`Other Immune-Mediated Disorders
`
` Immune-mediated disorders including skin reactions, lymphadenopathy,
`
`
`non-infectious colitis, and other immune-mediated disorders can occur
`
`
`
`with ZINBRYTA (5.2).
`
`
`
`
`
`
`These conditions may require treatment with systemic corticosteroids or
`
`
`
`immunosuppressive medication (5 1, 5.2).
`
`
`
`
`
`
`
`
`ZINBRYTA is available only through a restricted distribution program
`called the ZINBRYTA REMS Program (5.3).
`
`
`
` __________________
` _________________
`INDICATIONS AND USAGE
`ZINBRYTA is an interleukin-2 receptor blocking antibody indicated for the
`
`
`
`treatment of adult patients with relapsing forms of multiple sclerosis (MS).
`
`Because of its safety profile, the use of ZINBRYTA should generally be
`
`reserved for patients who have had an inadequate response to two or more
`
`
`
`drugs indicated for the treatment of MS. (1)
`
`
`
`
`_______________DOSAGE AND ADMINISTRATION
`
`
` ______________
`• Recommended dosage: 150 milligrams once monthly (2.1)
`
`
`
`
`
`• For subcutaneous use only (2.1)
`
`
`
`• Train patients in the proper technique for self-administration (2.2)
`
`
`
`
`
`
`
`
`
`1
`
`2
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE
`
`
`HEPATITIS AND OTHER IMMUNE-MEDIATED DISORDERS
`
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Information
`
`Important Administration Instructions
`2.2
`
`2.3 Assessment Prior to Initiating ZINBRYTA
`
`
`2.4 Laboratory Testing and Monitoring to Assess Safety after
`
`
`
`
`Initiating ZINBRYTA
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hepatic Injury
`
`5.2
`Immune-Mediated Disorders
`
`
`5.3 ZINBRYTA REMS Program
`
`
`5.4 Acute Hypersensitivity
`
`
`
`5.5
`Infections
`
`5.6 Depression and Suicide
`
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2
`Immunogenicity
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2 Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`6
`
`
`7
`
`8
`
`• Conduct laboratory tests at baseline and at periodic intervals to monitor for
`
`
`
`early signs of potentially serious adverse reactions (2.3, 2.4).
`
`
`
` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`Injection: 150 mg/mL solution in a single-dose prefilled syringe (3)
`
`
`
`
`
`___________________ CONTRAINDICATIONS ___________________
`
`
`
`• Pre-existing hepatic disease or hepatic impairment, including ALT or AST
`
`
`
`
`at least 2 times the ULN (4)
`
`
`
`• History of autoimmune hepatitis or other autoimmune condition involving
`
`
`
`
`the liver (4)
`
`• History of hypersensitivity to daclizumab or any other component of the
`
`
`
`formulation (4)
`
`
`_______________WARNINGS AND PRECAUTIONS _______________
`
`
`
`
`• Hypersensitivity Reactions: Risk of anaphylaxis and angioedema.
`
`
`
`
`
`Discontinue and do not re-start ZINBRYTA if anaphylaxis or other allergic
`
`
`reactions occur (5.4)
`
`
`• Infections: Increased risk of infections. If serious infection develops,
`
`
`
`
`
`
`consider withholding ZINBRYTA until infection resolves (5.5)
`
`
`• Depression and Suicide: Advise patients to immediately report symptoms
`
`
`
`
`
`
`of depression and/or suicidal ideation to their health care provider.
`
`
`
`
`Consider discontinuation if severe depression and/or suicidal ideation occur
`
`
`
`
`(5.6)
`
`___________________ ADVERSE REACTIONS ___________________
`
`
`
`
`The most common adverse reactions (incidence ≥5% and ≥2% higher
`
`
`incidence than comparator) reported for ZINBRYTA 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 (6.1)
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1­
`
`800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`---------------------------DRUG INTERACTIONS----------------------------------
`Hepatotoxic Drugs: Evaluate potential for increased risk of hepatotoxicity
`
`
`with concomitant use (7.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide
`
`
`
`
`
`Revised: 05/2016
`
`
`
`
`
`
`8.6 Hepatic Impairment
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`16.2 Storage and Handling
`
`
`16.3
`Instructions for Disposal
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`Reference ID: 3938318
`
`
`
`
`
`Biogen Exhibit 2163
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 32
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
`
` WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS and
`
`
` OTHER IMMUNE-MEDIATED DISORDERS
`
`
` • Hepatic Injury Including Autoimmune Hepatitis
`
` ZINBRYTA can cause severe liver injury including life-threatening events, liver failure,
`
`
`
` and autoimmune hepatitis. In clinical trials, 1 patient died due to autoimmune
` hepatitis. Liver injury, including autoimmune hepatitis, can occur at any time during
`
`
` treatment with ZINBRYTA, with cases reported up to 4 months after the last dose of
`
` ZINBRYTA.
`ZINBRYTA is contraindicated in patients with pre-existing hepatic disease or hepatic
`impairment [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`Prior to starting ZINBRYTA, obtain serum transaminases (ALT and AST) and
`
`bilirubin levels [see Dosage and Administration (2.3)].
`
`
`
`Test transaminase levels and total bilirubin monthly and assess before the next dose of
`
`
`
`
`
`ZINBRYTA. Follow transaminase levels and total bilirubin monthly for 6 months after
`
`
`
`the last dose of ZINBRYTA. In case of elevation in transaminases or total bilirubin,
`treatment interruption or discontinuation may be required [see Dosage and
`Administration (2.4) and Warnings and Precautions (5.1)].
`
`• Other Immune-Mediated Disorders
`
`
`In addition to autoimmune hepatitis, immune-mediated disorders such as skin
`
`
`
`reactions, lymphadenopathy, and non-infectious colitis can occur in patients treated
`
`with ZINBRYTA. Overall, serious immune-mediated conditions were observed in 5%
`
`
`of patients treated with ZINBRYTA [see Warnings and Precautions (5.2)].
`
`
`If a patient develops a serious immune-mediated disorder, consider stopping
`
`
`
`ZINBRYTA and refer the patient to a specialist to ensure comprehensive diagnostic
`evaluation and appropriate treatment.
`
`Some patients required systemic corticosteroids or other immunosuppressant treatment for
`
`autoimmune hepatitis or other immune-mediated disorders and continued this treatment
`
`after the last dose of ZINBRYTA [see Warnings and Precautions (5.1, 5.2)].
`
`
`Because of the risks of hepatic injury, including autoimmune hepatitis, and other immune-
`
`
`mediated disorders, ZINBRYTA is available only through a restricted program under a
`
`Risk Evaluation and Mitigation Strategy (REMS) called the ZINBRYTA REMS Program
`
`
`[see Warnings and Precautions (5.3)].
`
`
`
`
`
`
`•
`
`
`Reference ID: 3938318
`
`2
`
`
`Page 2 of 32
`
`

`

` 1
` INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`
` ZINBRYTA is indicated for the treatment of adult patients with relapsing forms of multiple
` sclerosis (MS). Because of its safety profile, the use of ZINBRYTA should generally be reserved
`
`
`
` for patients who have had an inadequate response to two or more drugs indicated for the
`
`
`
` treatment of MS.
`
`
`
`
`
` 2
`
`
`
` 2.1
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
` Dosing Information
`
` The recommended dosage of ZINBRYTA is 150 milligrams injected subcutaneously once
`
`
`
` monthly [see Dosage and Administration (2.3, 2.4)].
`
` Instruct patients to inject a missed dose as soon as possible but no more than two weeks late.
`
`
` After two weeks, skip the missed dose and take the next dose on schedule. Administer only one
`
`
` dose at a time.
`
`
`
`
`
` Important Administration Instructions
`
`
`
`
` 2.2
`
` ZINBRYTA is for subcutaneous use only.
`
`
` Train patients in the proper technique for self-administering subcutaneous injections using the
` prefilled syringe.
`
` Thirty minutes prior to injection, remove ZINBRYTA from the refrigerator to allow the drug to
`
`
`
` warm to room temperature. Do not use external heat sources such as hot water to warm
` ZINBRYTA. Do not place ZINBRYTA back into the refrigerator after allowing it to warm to
`
`
`
`
` room temperature [see How Supplied/Storage and Handling (16.2)].
`
` Parenteral drug products should be inspected visually for particulate matter and discoloration
`
` prior to administration, whenever solution and container permit. ZINBRYTA is a colorless to
`
`
` slightly yellow, clear to slightly opalescent solution. Do not use ZINBRYTA if it is cloudy or
`
`
`
`
` there are visible particles.
`
`
` Sites for injection include the thigh, abdomen, and back of the upper arm.
`
`
`
` Use each prefilled syringe one time and then place in a sharps disposal container for disposal
` according to community guidelines [see How Supplied/Storage and Handling (16.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Assessment Prior to Initiating ZINBRYTA
` 2.3
`
`
`
` Hepatic Assessment
`
` Prior to initiating ZINBRYTA, obtain and evaluate the following:
`
`
` • Serum transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase
`
`
`
`
`
` (AST)) and total bilirubin levels. Initiation of ZINBRYTA is contraindicated in patients with
`
`
`
` pre-existing hepatic disease or hepatic impairment including ALT or AST at least 2 times the
`
` ULN [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`
`
`Reference ID: 3938318
`
`
`
` 3
`
`
`Page 3 of 32
`
`

`

`
`
`
`
`
`
` Assessment for Tuberculosis and Other Infections
`
`
` • Evaluate patients at high risk for tuberculosis infection prior to initiating treatment with
`
`
`
`
` ZINBRYTA [see Warnings and Precautions (5.5)]. For patients testing positive for
`
`
`
` tuberculosis, treat tuberculosis by standard medical practice prior to therapy with
`
`
`
` ZINBRYTA.
` • Avoid initiating ZINBRYTA in patients with tuberculosis or other severe active infection
`
`
` [see Warnings and Precautions (5.5)].
`
` • Prior to initiation of ZINBRYTA, screen patients for Hepatitis B and C. ZINBRYTA is
`
`
`
` contraindicated in patients with pre-existing hepatic disease [see Contraindications (4)].
`
`
`
` Vaccinations
`Because vaccination with live vaccines is not recommended during treatment and up to 4 months
`
`after discontinuation of treatment, consider any necessary immunization with live vaccines prior
`
`
`
`to treatment with ZINBRYTA [see Warnings and Precautions (5.5)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.4 Laboratory Testing and Monitoring to Assess Safety after Initiating
`
` ZINBRYTA
` Conduct the following laboratory tests at periodic intervals to monitor for early signs of
`
` potentially serious adverse effects:
` Liver Tests
`
`Test transaminase levels and total bilirubin monthly and assess before the next dose of
`
`
`
`
`
`ZINBRYTA. Follow transaminase levels and total bilirubin monthly for 6 months after the last
`
`
`
`dose of ZINBRYTA. As shown in Table 1, interruption or discontinuation of ZINBRYTA
`
`
`therapy is recommended for management of certain liver test abnormalities [see Warnings and
`
`
`
`Precautions (5.1)].
`
`
`
`
`Reference ID: 3938318
`
`4
`
`
`
`Page 4 of 32
`
`

`

` Table 1: ZINBRYTA Treatment Modification for Liver Test Abnormalities
`
`
` Elevated Transaminases and/or Total Bilirubin
` [see Warnings and Precautions (5.1)]
`
`
` Recommendations
`
` Interrupt ZINBRYTA therapy and investigate for
`
`
` other etiologies of abnormal lab value(s).
`
` Lab Value(s)
`
`
`
` ALT or AST greater than 5 times ULN
`
` OR
`
`
`
`
`
` Total bilirubin greater than 2 times ULN
`
` OR
`
`
`
`
`
` ALT or AST greater than or equal to 3 but less
` than 5 times ULN and total bilirubin greater
`
`
`
`
`than 1.5 but less than 2 times ULN
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
` If no other etiologies are identified, then discontinue
`
` ZINBRYTA.
`
` If other etiologies are identified, re-assess the
`
`
`
`
` overall risk-benefit profile of ZINBRYTA in the
` patient and consider whether to resume ZINBRYTA
`
`
` when both AST or ALT are less than 2 times ULN
`
`
`
`
`
` and total bilirubin is less than or equal to ULN.
`
` In clinical trials, permanent discontinuation of therapy was required if the patient had liver test abnormalities
`
`
`
`
` resulting in suspension of study treatment for at least 8 consecutive weeks.
`
` ULN = upper limit of normal
`
`
`
`
`
`
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
` Injection: 150 mg/mL solution in a single-dose prefilled syringe.
` ZINBRYTA is a sterile, preservative-free, colorless to slightly yellow, clear to slightly
`
`
`
`
` opalescent solution.
`
`
`
` CONTRAINDICATIONS
` 4
`
`
` ZINBRYTA is contraindicated in patients with:
`
`
` • Pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2
`
`
` times the ULN, because ZINBRYTA could exacerbate existing liver dysfunction [see
`
`
`
` Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
`
`
`
` • A history of autoimmune hepatitis or other autoimmune condition involving the liver [see
`
`
`
` Warnings and Precautions (5.1)].
`
` • A history of hypersensitivity to daclizumab or any other components of the formulation.
`
`
`Use in such patients may result in anaphylaxis or life-threatening multi-organ
`hypersensitivity [see Warnings and Precautions (5.4)].
`
`
`
`
`
`
`
`
`
`Reference ID: 3938318
`
`5
`
`
`
`Page 5 of 32
`
`

`

`
`
` 5
`
`
`
` WARNINGS AND PRECAUTIONS
`
` 5.1
` Hepatic Injury
`
`
`
`
`
` ZINBRYTA can cause life-threatening severe liver injury, including liver failure and
`
` autoimmune hepatitis. In controlled studies, serious drug-related hepatic injury occurred in 0.7%
`
` of ZINBRYTA-treated patients compared with 0.4% of AVONEX-treated patients (Study 1) and
`
`
`
` in 1.0% of ZINBRYTA-treated patients compared with no injury in placebo patients (Study 2).
`
`
`
`
` Across all clinical studies (controlled and open-label), serious drug-related hepatic injury
`
`
`
` occurred in 1% of ZINBRYTA-treated patients, with monthly monitoring of transaminases and
`
`
`total bilirubin. The incidence of discontinuation due to drug related hepatic injury was 5% in
`ZINBRYTA-treated patients and 4% in AVONEX-treated patients.
`
`Autoimmune Hepatitis
`
`Across all clinical studies (controlled and open-label), 0.3% of ZINBRYTA-treated patients
`
`
`
`developed autoimmune hepatitis. One fatal case of autoimmune hepatitis occurred in a patient re-
`
`initiating ZINBRYTA after a planned 6 month treatment interruption period. This patient
`
`subsequently received two doses of ZINBRYTA in the presence of persisting alanine
`
`
`aminotransferase levels (ALT) more than 5 times the upper limit of normal (ULN).
`
`
`Transaminase and Total Bilirubin Elevations
`
`
`
`The incidence of increases in hepatic transaminases was greater in patients taking ZINBRYTA
`
`
`
`than in those taking AVONEX or placebo. The incidence of ALT or AST elevations above 5
`
`times the ULN was 6% in ZINBRYTA-treated patients compared with 3% in AVONEX-treated
`
`
`
`
`
`patients (Study 1) and 4% in ZINBRYTA-treated patients compared with 1% in patients on
`
`
`
`placebo (Study 2). Less than 1% of ZINBRYTA-treated patients had ALT or AST greater than
`
`
`
`
`
`
`20 times the ULN. Elevations of hepatic transaminases of at least 3 times the ULN combined
`with elevated bilirubin at least 2 times the ULN and alkaline phosphatase less than 2 times the
`
`
`ULN occurred in 0.7% of ZINBRYTA-treated patients compared with 0.1% of AVONEX-
`
`
`treated patients. In clinical trials, serum transaminase elevations occurred during treatment and
`
`
`
`up to 4 months after the last dose of ZINBRYTA.
`
`
`Monitoring
`
`
`
`
`Prior to starting treatment with ZINBRYTA, obtain serum transaminases (ALT and AST) and
`total bilirubin levels [see Contraindications (4)].
`
`
`
`
`
`
`
`Test transaminase levels and total bilirubin monthly and assess before the next dose of
`
`
`ZINBRYTA. Follow transaminase levels and total bilirubin monthly for 6 months after the last
`
`
`dose of ZINBRYTA.
`
`
`Treatment modifications are recommended based on serum transaminase and total bilirubin
`values [see Dosage and Administration (2.4)].
`
`
`
`If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g.,
`unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine),
`
`
`promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment
`
`with ZINBRYTA, as appropriate.
`
`
`Reference ID: 3938318
`
`6
`
`
`
`Page 6 of 32
`
`

`

`
`
`
`
`
` Patients with prolonged elevations of serum transaminases should be evaluated for other possible
`
` causes, such as infection, and a specialist should evaluate the patient [see Dosage and
` Administration (2.4)]. Discontinue ZINBRYTA if autoimmune hepatitis is suspected. Treatment
`
` of autoimmune hepatitis with systemic corticosteroids and other immunosuppressant drugs may
`
`
`
`
` be required. Some patients may need long-term immunosuppression.
`
`
`
`Risk of Hepatic Injury with Concomitant Use of Other Hepatotoxic Drugs
`Caution should be used when using hepatotoxic drugs, including non-prescription products,
`
`
`concomitantly with ZINBRYTA. Also, carefully consider the need for the use of herbal products
`
`or dietary supplements that can cause hepatotoxicity [see Drug Interactions (7.1)].
`
`
`
`
`
`
`
`
`
` Immune-Mediated Disorders
`
`
` 5.2
`
` Treatment with ZINBRYTA increases the risk of immune-mediated disorders, including
`
`
`
`autoimmune disorders such as autoimmune hepatitis. Across all clinical studies (controlled and
` open-label), immune-mediated disorders occurred in 28% of patients on ZINBRYTA, the most
`
`
`
`
` common of which were skin reactions and lymphadenopathy. In the active-control study (Study
` 1), immune-mediated disorders were observed in 32% of ZINBRYTA-treated patients compared
`
`
` with 12% for AVONEX-treated patients. In Study 1, serious immune-mediated disorders were
`
`
`
` observed in 4% of patients treated with ZINBRYTA compared with less than 1% for AVONEX-
`
`
` treated patients. In the placebo-control study (Study 2), immune-mediated disorders were
`
`
` observed in 13% of ZINBRYTA-treated patients compared with 7% of placebo-treated patients.
`
`
`In Study 2, serious immune-mediated disorders were observed in 0.5% of ZINBRYTA-treated
`
`
` patients and in 0.5% of placebo-treated patients. In some cases, patients had concurrent or
`
`
`
` sequential occurring disorders while taking ZINBRYTA.
`
`
`
` 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 ZINBRYTA 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
`
`ZINBRYTA and refer the patient to an appropriate specialist for further evaluation and
`
`treatment.
`
`Skin Reactions
`
`
`ZINBRYTA causes skin reactions. In clinical trials, skin reactions occurred in 37% of
`
`
`
`ZINBRYTA-treated patients compared with 19% of AVONEX-treated patients (Study 1) and in
`
`
`
`
`18% of ZINBRYTA-treated patients compared with 13% of patients on placebo (Study 2). Skin
`
`
`
`reactions occurred at any time during treatment with ZINBRYTA. Rashes occurred in 11% of
`
`
`ZINBRYTA-treated patients compared to 4% of AVONEX-treated patients, and in 7% of
`
`
`ZINBRYTA-treated patients compared to 3% of patients on placebo. Dermatitis occurred more
`
`
`frequently in ZINBRYTA-treated patients compared to AVONEX-treated patients or to patients
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`
`
`
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`Reference ID: 3938318
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`
`
`
` on placebo, and eczema was observed more frequently in ZINBRYTA-treated patients compared
` to AVONEX-treated patients [see Adverse Reactions (6.1)]. Psoriatic conditions occurred in 2%
`
`
` of ZINBRYTA-treated patients compared with 0.3% of AVONEX-treated patients.
`
`
`
`
`
`Photosensitivity also occurred.
` Serious skin reactions occurred in 2% of patients treated with ZINBRYTA compared with 0.1%
`
`
`
`
`
`
`
` of patients on AVONEX (Study 1) and in 1% of patients treated with ZINBRYTA 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 ZINBRYTA 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
`ZINBRYTA-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 ZINBRYTA. Discontinuation of
`
`
`
`ZINBRYTA may be appropriate.
`
`
`Lymphadenopathy
`
`ZINBRYTA increases the incidence of lymphadenopathy. In controlled studies,
`
`
`lymphadenopathy or lymphadenitis occurred in 6% of ZINBRYTA-treated patients compared
`
`
`with 1% of AVONEX-treated patients (Study 1) and in 2% of ZINBRYTA-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 ZINBRYTA and took a
`
`
`mean of 3 months to resolve. Lymphadenopathy resulted in discontinuation in 0.6 % of
`
`ZINBRYTA-treated patients.
`
`Some patients with lymphadenopathy underwent 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
`
`
`ZINBRYTA 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 ZINBRYTA. These include single organ or systemic multi-organ inflammatory
`
`
`
`reactions. Many events occurred in only one patient, and the relationship to ZINBRYTA is
`
`
`
`
`
`
`unknown [see Adverse Reactions (6.1)]. Some required treatment with systemic corticosteroids.
`
`
`
`Some required several months for resolution after the last dose of ZINBRYTA.
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`Reference ID: 3938318
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`For suspected immune-mediated disorders, ensure adequate evaluation to confirm etiology or to
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`
`
`exclude other causes. If a patient develops a serious immune-mediated disorder, consider
`
`stopping ZINBRYTA and refer the patient to an appropriate specialist for further evaluation and
`
`treatment.
`
`
`
`
`
`
` 5.3
`
`
` ZINBRYTA REMS Program
` ZINBRYTA is available only through a restricted program under a Risk Evaluation and
`
`
`
`
`
` Mitigation Strategy (REMS) called the ZINBRYTA 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 ZINBRYTA 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 ZINBRYTA.
`Further information, including a list of qualified pharmacies/distributors, is available at 1-800­
`
` -456-2255
`
`
` 5.4
`
` ZINBRYTA can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time
`
`
`
` during treatment. Discontinue and do not re-start ZINBRYTA if anaphylaxis or other allergic
`
`
` reactions occur [see Contraindications (4)].
`
`
`
`
`
`
`
`
`
` Acute Hypersensitivity
`
` 5.5
`
`
` Infections
`
` ZINBRYTA increases the risk for infections. In controlled trials, infections occurred in 65% of
`
` ZINBRYTA-treated patients compared with 57% of AVONEX-treated patients (Study 1) and in
`
`
`
` 50% of ZINBRYTA-treated patients compared with 44% of patients taking placebo (Study 2).
`
`
`
`
` Serious infections occurred in 4% of ZINBRYTA-treated patients compared with 2% of
`
`
`
` AVONEX-treated patients (Study 1) and in 3% of ZINBRYTA-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
`
` ZINBRYTA. For patients testing positive for tuberculosis, treat by standard medical practice
`
` prior to therapy with ZINBRYTA [see Dosage and Administration (2.3)].
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`Reference ID: 3938318
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` Avoid initiating ZINBRYTA in patients with severe active infection until the infection is fully
`
`
`
` controlled. If serious infection develops, consider withholding treatment with ZINBRYTA until
`
`
` the infection resolves.
`
`
`Vaccinations
`The safety of immunization with live viral vaccines during treatment with ZINBRYTA has not
`
`been studied. Vaccination with live vaccines is not recommended during treatment and up to 4
`
`
`months after discontinuation of ZINBRYTA [see Dosage and Administration (2.3)].
`
`
`
`
`
` 5.6
`
`
`
` Depression and Suicide
`
`
` Depression-related events occurred more frequently in patients receiving ZINBRYTA than in
`
`
` patients receiving AVONEX or placebo. In controlled trials, depression-related events occurred
`
`
`
` in 10% of ZINBRYTA-treated patients compared with 8% of AVONEX-treated patients (Study
`
` 1) and in 7% of ZINBRYTA-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 ZINBRYTA-treated patients and in 0.7% of AVONEX-treated
`
`
`
` patients. None occurred in Study 2 (placebo-controlled).
`
`
`
`
` Administer ZINBRYTA 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
`
` ZINBRYTA.
`
`
`
`
`
`
`
` ADVERSE REACTIONS
` 6
`
`
` 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)]
`
`
`
`
`
`
`
`
`
` Clinical Trials Experience
` 6.1
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
` observed in the clinical trials of ZINBRYTA 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 ZINBRYTA for a total of 5214 person-years. Of these patients, 1576
`
`
`
`
`
` received ZINBRYTA for at least 1 year, 1259 for at least 2 years, and 888 for at least 3 years. In
`
`
`
`
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`Reference ID: 3938318
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`10
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`Page 10 of 32
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`

`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 ZINBRYTA (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 ZINBRYTA; 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 ZINBRYTA 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 ZINBRYTA-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 ZINBRYTA 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 ZINBRYTA 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 en