Daclizumab

• Daclizumab (Zinbryta) is an injectable medication used for treating multiple sclerosis (MS). Its mechanism of action is not completely understood. Available data suggests that it may work by modifying immune processes that may be responsible for causing MS by interfering with the activation of lymphocytes (a type of white blood cell) that cause inflammation and destruction of nerves in patients with MS. Daclizumab does not cure MS. It decreases the number of MS flares and lesions.
• The FDA approved daclizumab in May, 2016.

Common side effects include:

• Cold symptoms
• Upper respiratory tract infection
• Rash
• Flu
• Dermatitis
• Throat pain
• Bronchitis
• Eczema
• Depression
• Sore throat
• Increased alanine aminotransferase (ALT)

Other side effects include:

• Tonsillitis
• Acne
• Anemia
• Fever

Other less common side effects include:

• Increased levels of liver enzymes
• Diarrhea
• Dry skin
• Skin redness (erythema)
• Folliculitis
• Psoriasis
• Skin exfoliation
• Toxic skin eruption
• Viral infection

Possible serious side effects include:

• Liver damage
• Immune mediated disorders (for example, skin reactions, colitis)
• Serious allergic reactions (anaphylaxis, angioedema)
• Severe infections
• Depression
• Suicidal thoughts, Suicide
• Decreased numbers of white blood cells
• Severe skin reactions
• Non-infectious colitis

SC Preparation

Train patients in the proper technique for self-administering SC injections using the prefilled syringe

30 minutes prior to injection, remove daclizumab from the refrigerator to allow the drug to warm to room temperature

Do not use external heat sources such as hot water to warm the prefilled syringe

Do not place daclizumab back into the refrigerator after allowing it to warm to room temperature

Parenteral drug products should be inspected visually for particulate matter and discoloration

Solution should appear as colorless to slightly yellow and clear to slightly opalescent

Do not use if solution is cloudy or there are visible particles

SC Administration

For subcutaneous (SC) use only

Sites for injection include the thigh, abdomen, and back of the upper arm

Use each prefilled syringe 1 time and then place in a sharps disposal container for disposal according to community guidelines

Missed dose

• Instruct patients to inject a missed dose as soon as possible but no more than 2 weeks late
• After 2 weeks, skip the missed dose and take the next dose on schedule
• Administer only 1 dose at a time; do not double the dose

Storage

Refrigerate between 2-8°C (36-46°F) in the original carton to protect from light

Do not freeze; discard if frozen

Do not expose to temperatures >30°C (86°F)

If refrigeration is unavailable, may store protected from light up to 30°C (86°F) for a period up to 30 days

Do not place drug back into the refrigerator after allowing it to warm to room temperature

Discard after 30 days without refrigeration

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

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Daclizumab is injected under the skin. You may be shown how to use injections at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of used needles and syringes.

Daclizumab is usually injected once a month. Follow your doctor's dosing instructions very carefully.

Daclizumab comes with a Medication Guide and a Patient Wallet Card that lists the symptoms of liver or immune system problems. Read this information carefully and carry the Wallet Card with you at all times so you will know what symptoms to watch for.

You will need blood tests to check your liver function every month while you are using daclizumab. Your next dose may be delayed based on the results of these tests.

You will also need frequent liver function tests for 6 months after you stop using this medicine.

Store daclizumab in the original carton in a refrigerator. Protect from heat and light. Do not freeze daclizumab, and do not use the medicine if it does freeze.

Before injecting your dose, take one vial out of the refrigerator and allow it to reach room temperature for 30 minutes. Do not heat the medicine in a microwave or with hot water. Do not put the vial back into the refrigerator after leaving it at room temperature.

Do not use daclizumab if it looks cloudy or has particles in it. Call your pharmacist for new medication.

Daclizumab may be stored in the original carton at room temperature for up to 30 days. Once the medicine has reached room temperature, you should not put it back into the refrigerator.

Each single-use prefilled syringe is for one use only. Throw away after one use, even if there is still some medicine left inside.

Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Get emergency medical help if you have signs of an allergic reaction: 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 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.

General

• Evaluate serum aminotransferase (ALT and AST) and total bilirubin concentrations prior to initiating therapy, then monthly before each dose is administered and for 6 months after discontinuance of therapy.1 (See Hepatic Injury under Cautions.)

• Evaluate for tuberculosis infection in patients at high risk and treat appropriately prior to initiating therapy.1 (See Infectious Complications under Cautions.)

• Screen all patients for hepatitis B and C infection prior to initiating therapy.1 (See Contraindications under Cautions.)

• Complete any necessary immunizations with live vaccines prior to initiating therapy.1

Restricted Distribution Program

• Daclizumab is available only through the Zinbryta REMS Program.1 Clinicians, pharmacies, and patients must be enrolled and meet all conditions of this program before they can prescribe, dispense, or receive the drug.1 8

• Additional information available at 800-456-2255 or .1 8

Administration

Administer by sub-Q injection only.1 7

If a dose is missed, administer as soon as possible; however, if >2 weeks have elapsed, omit missed dose and resume regular dosing schedule.1 6

Sub-Q Administration

Administer once monthly by sub-Q injection into thigh, abdomen, or back of upper arm using a single-dose prefilled syringe (supplied by manufacturer).1

Instruct patients on proper techniques for self-administration.1 (See Advice to Patients.)

At least 30 minutes prior to administration, allow prefilled syringe to reach room temperature.1 7

For single-use only; discard after use.1 7

Dosage

Adults

150 mg once monthly.1

A higher dosage of 300 mg once monthly not shown in clinical studies to provide additional clinical benefit.3 4

Interrupt therapy in patients with ALT or AST >5 times the ULN, total bilirubin >2 times the ULN, or ALT or AST ≥3 times but <5 times the ULN with total bilirubin >1.5 times but <2 times the ULN.1

Evaluate patient for other possible causes of liver function test abnormalities.1 Permanently discontinue therapy if no other etiologies identified.1 If other etiologies identified, consider risks and benefits of continuing daclizumab therapy; may resume therapy when both ALT and AST decrease to <2 times the ULN and total bilirubin returns to within normal limits.1

In clinical studies, permanent discontinuance of therapy was required if a patient had liver function test abnormalities resulting in treatment suspension for ≥8 consecutive weeks.1

Special Populations

Hepatic Impairment

Contraindicated in patients with hepatic impairment.1

Renal Impairment

No dosage adjustment required.4

Geriatric Patients

No specific dosage recommendations at this time.1

Contraindications

• Preexisting hepatic disease or hepatic impairment (e.g., ALT or AST ≥2 times the ULN).1

• History of autoimmune hepatitis or other autoimmune condition involving the liver.1

• Known hypersensitivity to daclizumab or any ingredients in the formulation.1

Warnings/Precautions

Warnings

Severe, sometimes fatal hepatic injury, including liver failure and autoimmune hepatitis, reported.1 2 23 (See Boxed Warning.) May occur at any time during therapy; has been reported up to 4 months after discontinuance of the drug.1

Monitor serum aminotransferase (ALT and AST) and total bilirubin concentrations prior to initiating therapy; continue to monitor monthly before each dose is administered and for 6 months after discontinuance of therapy.1 If manifestations suggestive of hepatotoxicity (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine) develop at any time during therapy, evaluate liver function tests promptly.1 Temporary interruption or permanent discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

If prolonged elevations of serum aminotransferase concentrations occur, investigate other potential causes (e,g., infection) and refer patient to a specialist.1

Discontinue therapy if autoimmune hepatitis is suspected.1 Treatment with systemic corticosteroids and other immunosuppressants may be necessary; some patients may require long-term immunosuppression.1

In addition to autoimmune hepatitis, other immune-mediated disorders including skin reactions (see Skin Reactions under Cautions), lymphadenopathy (see Lymphadenopathy under Cautions), and noninfectious colitis (see Noninfectious Colitis under Cautions) reported.1 26 27

In some cases, patients required invasive procedures for diagnosis (e.g., colonoscopy, biopsy), hospitalization for fluid replacement or blood transfusion, or prolonged treatment with systemic corticosteroids or immunosuppressants.1 Resolution did not always occur after discontinuance of the drug.1

Monitor closely for development of immune-mediated disorders; if such a disorder is suspected, adequately evaluate patient to confirm etiology or exclude other causes.1 If a serious immune-mediated disorder develops, consider drug discontinuance and patient referral to a specialist.1

Skin reactions, which can be serious and sometimes fatal, reported; such reactions include rash, dermatitis, eczema, psoriasis, and photosensitivity, and may occur at any time during therapy.1 2 3 11 27 (See Other Immune-mediated Disorders under Cautions.)

Daclizumab may exacerbate preexisting dermatologic conditions such as rash, dermatitis, eczema, or psoriasis.1 11

Treatment with topical or systemic corticosteroids or immunosuppressants (e.g., tacrolimus) may be required.1

Patients who develop a serious diffuse or inflammatory rash should be evaluated by a dermatologist before the next dose of daclizumab is administered; discontinuance of therapy may be necessary.1

Lymphadenopathy or lymphadenitis, including serious related events (e.g., infections, benign salivary neoplasm, skin reactions, thrombocytopenia, interstitial lung changes), reported; may occur at any time during therapy.1 (See Other Immune-mediated Disorders under Cautions.) Majority of cases resolved regardless of whether daclizumab was continued; mean time to resolution was 3 months.1

Serious noninfectious colitis reported.1 (See Other Immune-mediated Disorders under Cautions.) Consider referral to a specialist in patients who develop manifestations (e.g., abdominal pain, fever, prolonged diarrhea).1

Other Warnings/Precautions

Anaphylaxis, angioedema, and urticaria can occur after the first dose or at any time during therapy.1 Permanently discontinue if anaphylaxis or other allergic reaction occurs.1 (See Contraindications under Cautions.)

Increased risk of infections.1 2 3 Most commonly reported infections include upper respiratory tract, urinary tract, and viral infections.1

Delay initiation of therapy in patients with severe active infection until infection is fully controlled.1 If a patient develops a serious infection during daclizumab therapy, consider withholding treatment until infection is resolved.1

Tuberculosis infection reported in endemic regions.1 Screen patients at high risk for tuberculosis and treat as clinically appropriate prior to initiating therapy.1

Depression-related events, including suicidal ideation and suicide attempt, reported.1

Use with caution in patients with a history of or current depressive disorders.1 If severe depression or suicidal ideation occurs, consider discontinuing therapy.1

Potential for immunogenicity; development of anti-daclizumab antibodies (including neutralizing antibodies) reported.1 3 Increased drug clearance reported in patients with neutralizing antibodies; however, effects of antibody development on clinical response, adverse reactions, or pharmacodynamic activity not observed.1

Specific Populations

No adequate data in pregnant women;1 9 limited data from clinical trials do not suggest an increased risk of adverse fetal or maternal outcomes.9

Increased embryofetal death and reduced fetal growth demonstrated in animals at dose exposures >30 times those achieved with recommended human doses.1

Not known whether distributed into human milk; distributed into milk in monkeys.1 Consider benefits of breast-feeding and importance of daclizumab to the woman; also consider potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Safety and efficacy not established in patients <17 years of age.1 Use not recommended.1

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Contraindicated in patients with hepatic impairment since such patients may be at increased risk for daclizumab-induced hepatotoxicity.1 (See Contraindications under Cautions.)

Renal elimination not expected;1 4 dosage adjustment not necessary in patients with renal impairment.4

Common Adverse Effects

Nasopharyngitis,1 2 upper respiratory tract infection,1 2 3 rash,1 2 3 eczema,1 2 influenza,1 dermatitis,1 oropharyngeal pain,1 bronchitis,1 pharyngitis,1 3 depression,1 lymphadenopathy,1 increased ALT concentrations.1

• Importance of patients reading the manufacturer's patient information (medication guide) and instructions for use before initiating daclizumab therapy and each time the prescription is refilled.1 6 7

• Risk of severe hepatic injury.1 6 Importance of advising patients to immediately inform their clinician if they experience any symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine).1 6

• Risk of developing immune-mediated disorders that can affect any organ system, including dermatologic reactions, lymphadenopathy, and noninfectious colitis.1 6 Importance of advising patients to immediately seek medical attention if dermatologic reactions occur and to report any manifestations of lymphadenopathy (e.g., painful or swollen lymph nodes) or colitis (e.g., abdominal pain, bloody stools, prolonged diarrhea).1 6

• Importance of advising patients that daclizumab is available only through a restricted distribution program called the Zinbryta REMS Program.1 6 Inform patients of the requirements of the program and provide them with information on how to obtain the drug from a certified pharmacy.1 6 Advise patients to carry the patient wallet card (which contains important information about the drug and describes symptoms that should prompt immediate medical attention) with them at all times.1 6

• Risk of hypersensitivity reactions, including anaphylaxis.1 6 Importance of advising patients to seek immediate medical attention if any symptoms of hypersensitivity occur.1 6

• Risk of infections; importance of advising patients to immediately contact their clinician if they develop any signs or symptoms of infection.1 6

• Importance of informing patients that depression and suicidal ideation have occurred with daclizumab therapy.1 Importance of patients immediately notifying their clinician if symptoms of new or worsening depression or suicidal ideation occur.1 6

• Importance of instructing patients regarding proper methods of self injection of daclizumab, including the use of aseptic technique.1 Importance of providing instructions on the appropriate use, storage, and disposal of syringes and needles.1 7

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.6

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., liver disease, skin conditions, tuberculosis).1 6

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

• If you have an allergy to daclizumab or any other part of daclizumab.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have ever had any of these health problems: Autoimmune hepatitis or liver disease.
• If you have TB (tuberculosis), talk with your doctor.
• If you have an infection.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take daclizumab with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

There are no dosage adjustments provided in the manufacturer’s labeling.

Get emergency medical help if you have signs of an allergic reaction: 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 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.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Daclizumab is injected under the skin. You may be shown how to use injections at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of used needles and syringes.

Daclizumab is usually injected once a month. Follow your doctor's dosing instructions very carefully.

Daclizumab comes with a Medication Guide and a Patient Wallet Card that lists the symptoms of liver or immune system problems. Read this information carefully and carry the Wallet Card with you at all times so you will know what symptoms to watch for.

You will need blood tests to check your liver function every month while you are using daclizumab. Your next dose may be delayed based on the results of these tests.

You will also need frequent liver function tests for 6 months after you stop using this medicine.

Store daclizumab in the original carton in a refrigerator. Protect from heat and light. Do not freeze daclizumab, and do not use the medicine if it does freeze.

Before injecting your dose, take one vial out of the refrigerator and allow it to reach room temperature for 30 minutes. Do not heat the medicine in a microwave or with hot water. Do not put the vial back into the refrigerator after leaving it at room temperature.

Do not use daclizumab if it looks cloudy or has particles in it. Call your pharmacist for new medication.

Daclizumab may be stored in the original carton at room temperature for up to 30 days. Once the medicine has reached room temperature, you should not put it back into the refrigerator.

Each single-use prefilled syringe is for one use only. Throw away after one use, even if there is still some medicine left inside.

Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

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

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.

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

-Preexisting hepatic impairment (including ALT or AST at least 2 times the ULN): Contraindicated
-A history of autoimmune hepatitis or other autoimmune condition involving the liver: Contraindicated
-Clinical trials did not include patients with ALT or AST more than 2 times the ULN.

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for daclizumab. It includes a communication plan, elements to assure safe use, and an implementation system. For additional informationhttp://www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:
WARNING: HEPATIC INJURY INCLUDING AUTOIMMUNE HEPATITIS AND OTHER IMMUNE-MEDIATED DISORDERS:
-This drug can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. This can occur at any time during treatment and has been reported up to 4 months after the last dose. Therapy is contraindicated in patients with preexisting hepatic disease or impairment. Prior to starting therapy, obtain serum transaminases (ALT and AST) and bilirubin levels. Test transaminase levels and total bilirubin monthly during therapy and for 6 months after the last dose. In case of elevation in transaminases or total bilirubin, therapy interruption or discontinuation may be necessary.
-Other Immune-Mediated Disorders: Skin reactions, lymphadenopathy, and non-infectious colitis have occurred in 5% of patients taking this drug. If a patient develops a serious immune-mediated disorder, consider discontinuing therapy and referring the patient to a specialist.
-Some patients may require systemic corticosteroids or other immunosuppressant treatment for autoimmune hepatitis or other immune-mediated disorders.

Safety and efficacy have not been established in patients younger than 17 years.

Consult WARNINGS section for additional precautions.