Zinbryta

Included as part of the PRECAUTIONS section.

Zinbryta comes as a prefilled, single-dose syringe.

It's injected under the skin of your thigh, your stomach, or the back of your upper arm.

This drug should be administered once every month (every four weeks).

Follow your doctor's instructions carefully when giving yourself a dose of Zinbryta.

Call your doctor if you have any questions about how to inject this medicine.

Zinbryta should be stored in the refrigerator. Don't freeze this medicine.

Zinbryta Overdose

If you suspect an overdose or Zinbryta, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Zinbryta

If you miss a dose of Zinbryta, inject it as soon as possible if it's within two weeks of your missed dose.

If more than two weeks have passed, skip your missed dose. Then inject your next dose at the regularly scheduled time.

Don't inject two doses of Zinbryta at once.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take hepatotoxic drugs such as:

• acetaminophen (Tylenol)
• isonaizid (Nydrazid)
• ketoconazole (Nizoral)
• fluconazole (Diflucan)
• antiretrovirals
  • efavirenz/emtricitabine/tenofovir (Atripla)
  • rilpivirine (Edurant)
  • emtricitabine (Emtriva)
  • elvitegravir, cobicistat, emtricitabine, and tenofovir (Stribild)
  • tenofovir and emtricitabine (Truvada)
  • tenofovir (Viread)
  • adefovir (Hepsera)
• aspirin and other NSAIDs (nonsteroidal anti-inflammatory drugs) such as
  • celecoxib (Celebrex)
  • diclofenac (Cambia, Cataflam, Flector, Voltaren, Zipsor and others)
  • etodolac (Lodine)
  • ibuprofen (Advil, Motrin, Nuprin)
  • indomethacin (Indocin, Indocin SR)
  • ketoprofen (Orudis, Actron, Oruvail)
  • ketorolac (Toradol)
  • meloxicam (Mobic)
  • nabumetone (Relafen)
  • naproxen (Naprosyn)
  • naproxen sodium (Aleve, Anaprox, Naprelan)
  • oxaprozin (Daypro)
  • piroxicam (Feldene)

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.

This is not a complete list of Zinbryta drug interactions. Ask your doctor or pharmacist for more information.

Before using Zinbryta, tell your healthcare provider if you:

• have or have had liver problems
• have or have had skin problems including eczema or psoriasis
• have tuberculosis
• have an active infection
• are planning to receive a vaccine
• have or have had depression
• are pregnant or plan to become pregnant. It is not known if Zinbryta will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Zinbryta passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use Zinbryta.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using Zinbryta with other medicines can cause serious side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

Tell your doctor if you are pregnant or plan to become pregnant.

In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended dose of Zinbryta for the treatment of multiple sclerosis is 150 mg injected subcutaneously once monthly.

Do not receive a "live" vaccine while using daclizumab and for at least 4 months after your last dose. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bladder pain
• blistering, crusting, irritation, itching, or reddening of the skin
• bloody or cloudy urine
• body aches or pain
• cough or hoarseness
• cracked, dry, or scaly skin
• difficult, burning, or painful urination
• difficulty with breathing
• discouragement
• ear congestion
• feeling sad or empty
• fever or chills
• frequent urge to urinate
• headache
• irritability
• lack of appetite
• loss of interest or pleasure
• loss of voice
• lower back or side pain
• nasal congestion
• painful or difficult urination
• rash
• runny nose
• sneezing
• sore throat
• swelling
• swollen, painful, or tender lymph glands in the neck, armpit, or groin
• trouble concentrating
• trouble sleeping
• unusual tiredness or weakness

• Dark urine
• general feeling of tiredness or weakness
• light-colored stools
• persistent loss of appetite
• right upper quadrant tenderness
• stomach pain, continuing
• vomiting
• yellow eyes or skin

• Thoughts or attempts at killing oneself
• watery or bloody diarrhea

• Dizziness
• fast heartbeat
• hives or welts
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blemishes on the skin
• pimples
• seizures

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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.

Hepatic Injury

Zinbryta can cause severe liver injury, including autoimmune hepatitis and liver failure. Fatal cases have occurred. 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 1.7% 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.

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 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).

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 [see Drug Interactions (7.1)].

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

Early identification of elevated liver enzymes may decrease the risk of a serious outcome. 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)].

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 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.

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

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 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. 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. 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.

Autoimmune Hemolytic Anemia

Across all clinical studies (controlled and open-label), autoimmune hemolytic anemia occurred in <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

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 [see Adverse Reactions (6.1)]. 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.

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.

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.

Acute Hypersensitivity

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)].

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.

Cytomegalovirus (CMV) infections (hepatitis and pneumonia) occurred in Zinbryta-treated patients in clinical trials.

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)].

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)].

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.

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)].

Use the missed dose as soon as you remember. If you are more than 2 weeks late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Get emergency medical help if you have signs of an allergic reaction to Zinbryta: hives, rash, fever; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• any type of infection - sudden weakness or ill feeling, fever, chills, sore throat, cold or flu symptoms, pain or burning when you urinate; or

• symptoms of depression - sadness, crying spells, drowsiness, trouble concentrating, anger, aggression, feeling hopeless or irritable, or having thoughts about suicide or hurting yourself.

Your treatment may be delayed if you have certain side effects.

Common Zinbryta side effects may include:

• cold symptoms (stuffy nose, sinus pain, sore throat);

• flu symptoms (fever, body aches, sore throat, swollen glands);

• cough, chest tightness;

• mouth pain;

• depressed mood;

• rash or itching;

• dry flaky skin; or

• abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to daclizumab: intravenous solution, subcutaneous solution

Cardiovascular

Common (1% to 10%): Lymphadenopathy, lymphadenitis[Ref]

Dermatologic

Very common (10% or more): Rash (i.e., erythematous rash, exfoliative rash, macular rash, maculopapular rash, papular rash, pruritic rash, rash, vesicular rash) (11%)
Common (1% to 10%): Dermatitis (i.e., allergic dermatitis, atopic dermatitis, bullous dermatitis, dermatitis, exfoliative dermatitis, seborrheic dermatitis, eczema, allergic dermatitis), folliculitis, acne, psoriasis, erythema, pruritus, dry skin
Uncommon (0.1% to 1%): Toxic skin eruption, eczema nummular[Ref]

Gastrointestinal

Common (1% to 10%): Tonsillitis, diarrhea
Frequency not reported: Colitis[Ref]

Hematologic

Common (1% to 10%): Anemia, lymphocyte count decreased[Ref]

Hypersensitivity

Frequency not reported: Anaphylaxis[Ref]

Respiratory

Very common (10% or more): Nasopharyngitis (25%), upper respiratory tract infection (17%)
Common (1% to 10%): Bronchitis, pneumonia, laryngitis, rhinitis[Ref]

Psychiatric

Common (1% to 10%): Depression[Ref]

Other

Common (1% to 10%): Oropharyngeal pain, pyrexia[Ref]

Hepatic

Common (1% to 10%): ALT increased, AST increased, liver function test abnormal, hepatic enzymes increased[Ref]

Immunologic

Common (1% to 10%): Influenza, viral infection[Ref]

Some side effects of Zinbryta may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.