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Daclizumab

Pronunciation

(dac KLYE zue mab)

Index Terms

  • Anti-Tac Monoclonal Antibody
  • Dacliximab
  • Daclizumab High Yield Process
  • Daclizumab HYP
  • MOAB anti-Tac
  • Zinbryta

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Zinbryta: 150 mg/mL (1 mL)

Brand Names: U.S.

  • Zinbryta

Pharmacologic Category

  • Immunosuppressant Agent
  • Interleukin-2 Inhibitor
  • Monoclonal Antibody

Pharmacology

Daclizumab is a humanized monoclonal antibody which binds to the CD25 subunit of the high-affinity interleukin-2 (IL-2) receptor to prevent signaling at the high-affinity IL-2 receptor while allowing increased IL-2 availability for signaling at the intermediate-affinity IL-2 receptor (Gold 2013, Kappos 2015). Because IL-2 has a role in activating and regulating the immune system; CD25 antagonism may result in therapeutic benefit in multiple sclerosis (Gold 2013).

Distribution

Vd: SubQ: ~6.34 L

Metabolism

Catabolized to peptides and amino acids

Time to Peak

SubQ: 5 to 7 days

Half-Life Elimination

SubQ: 21 days

Use: Labeled Indications

Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis (MS) in adult patients. Daclizumab should generally be reserved for patients who have had an inadequate response to 2 or more medications indicated for the treatment of MS.

Contraindications

Hypersensitivity to daclizumab or any component of the formulation; preexisting hepatic disease or hepatic impairment, including ALT or AST at least 2 times the ULN; history of autoimmune hepatitis or other autoimmune condition involving the liver

Dosing: Adult

Note: Screen patients for hepatitis B and C prior to treatment initiation. Avoid initiating treatment in patients with severe active infection (including tuberculosis).

Multiple sclerosis, relapsing: SubQ: 150 mg once monthly (Gold 2013, Kappos 2015).

Missed dose: Administer a missed dose as soon as possible, but no more than 2 weeks late; after 2 weeks, skip the missed dose and administer the next dose on schedule. Administer only 1 dose at a time.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

Preexisting hepatic disease or impairment, including ALT or AST ≥2 times ULN or history of autoimmune hepatitis (or other autoimmune condition involving the liver): Use is contraindicated.

Hepatotoxicity during treatment: ALT or AST >5 times ULN or total bilirubin >2 times ULN or ALT or AST ≥3 to <5 times ULN AND total bilirubin >1.5 to <2 times ULN: Interrupt treatment and investigate for other etiologies of abnormal lab value. If no other etiologies are identified, discontinue daclizumab. If other etiologies are identified, evaluate overall risk versus benefit of daclizumab relative to the patient and consider if appropriate to resume daclizumab treatment when BOTH AST or ALT <2 times ULN AND total bilirubin ≤ULN. In clinical trials, treatment was permanently discontinued if liver function test abnormalities resulted in a treatment suspension of at least 8 consecutive weeks.

Suspected autoimmune hepatitis: Promptly discontinue daclizumab; may require systemic corticosteroids and other immunosuppressant therapy

Dosing: Adjustment for Toxicity

Anaphylaxis or other allergic reaction: Discontinue treatment; do not re-initiate.

Depression (severe) or suicidal ideation: Consider discontinuing treatment.

Dermatologic toxicity: Serious diffuse or inflammatory rashes: Discontinuation may be appropriate; consider referral to a dermatologist for evaluation prior to the next dose.

Immune-mediated disorders, serious: Consider discontinuing daclizumab and refer to a specialist; may require systemic corticosteroids or other immunosuppressant treatment.

Infection (serious): Consider withholding daclizumab until infection resolves.

Reconstitution

Allow to warm to room temperature by removing prefilled syringe from the refrigerator 30 minutes prior to injection. Do not use external heat sources (eg, hot water) to warm daclizumab. Do not place back into refrigerator after allowing product to warm to room temperature.

Administration

For subcutaneous administration only. Administer subcutaneously into the thigh, abdomen, or back of the upper arm.

Remove prefilled syringe from refrigerator and allow to warm to room temperature 30 minutes prior to injection. Patients may be trained on proper technique for self-administration. Use each prefilled syringe one time and then place in a sharps container for disposal according to community guidelines.

Storage

Store at 2°C to 8°C (36°F to 46°F). Do not expose to temperatures above 30°C (86°F). Do not freeze (discard if frozen). Keep in the original carton to protect from light.

If refrigeration is unavailable, may be stored protected from light for up to 30 days at up to 30°C (86°F). Do not place back into the refrigerator after allowing it to warm to room temperature. Discard after 30 days without refrigeration.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Daclizumab may enhance the adverse/toxic effect of Vaccines (Live). Daclizumab may diminish the therapeutic effect of Vaccines (Live). Avoid combination

Adverse Reactions

>10%:

Dermatologic: Allergic skin reaction (18% to 37%), skin rash (7% to 11%)

Immunologic: Autoimmune disease (13% to 32%)

Infection: Infection (50% to 65%)

Respiratory: Nasopharyngitis (25%), upper respiratory tract infection (9% to 17%)

1% to 10%:

Central nervous system: Depression (7% to 10%), seizure (1%)

Dermatologic: Dermatitis (3% to 9%), eczema (5%), acne vulgaris (3%)

Hematologic & oncologic: Lymphadenopathy (5%), anemia (3%)

Hepatic: Increased serum ALT (5% to 6%), increased serum AST (3% to 6%), hepatic injury (≤1%)

Infection: Influenza (9%)

Respiratory: Oropharyngeal pain (8%), bronchitis (7%), pharyngitis (6%), rhinitis (4%), tonsillitis (4%)

Miscellaneous: Fever (3%)

Frequency not defined:

Dermatologic: Desquamation, erythema, folliculitis, pruritus, psoriasis, skin photosensitivity, skin rash (toxic), xeroderma

Gastrointestinal: Diarrhea

Hematologic & oncologic: Decreased absolute lymphocyte count, lymphadenitis

Hepatic: Abnormal hepatic function tests, increased liver enzymes

Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, angioedema, and urticaria)

Infection: Viral infection

Respiratory: Laryngitis, pneumonia, respiratory tract infection

<1% (Limited to important or life-threatening): Autoimmune hepatitis, colitis (serious; noninfectious), increased serum alkaline phosphatase (<2 x ULN), increased serum bilirubin (≥2 x ULN), increased serum transaminases (≥3 x ULN), malignant neoplasm of breast (more common in women), suicidal ideation

ALERT: U.S. Boxed Warning

Hepatotoxicity including autoimmune hepatitis:

Daclizumab can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis. In clinical trials, one patient died due to autoimmune hepatitis. Liver injury, including autoimmune hepatitis, can occur at any time during treatment with daclizumab, with cases reported up to 4 months after the last dose of daclizumab.

Daclizumab is contraindicated in patients with preexisting hepatic disease or hepatic impairment. Prior to starting daclizumab, obtain serum transaminases (ALT and AST) and bilirubin levels.

Test transaminase levels and total bilirubin monthly and assess before the next dose of daclizumab. Follow transaminase levels and total bilirubin monthly for 6 months after the last dose of daclizumab. In case of elevation in transaminases or total bilirubin, treatment interruption or discontinuation may be required.

Other immune-mediated disorders:

In addition to autoimmune hepatitis, immune-mediated disorders such as skin reactions, lymphadenopathy, and noninfectious colitis can occur in patients treated with daclizumab. Overall, serious immune-mediated conditions were observed in 5% of patients treated with daclizumab. If a patient develops a serious immune-mediated disorder, consider stopping daclizumab and refer the patient to a specialist to ensure comprehensive diagnostic evaluation and appropriate treatment.

Systemic corticosteroids:

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 daclizumab.

REMS Program:

Because of the risks of hepatic injury, including autoimmune hepatitis, and other immune-mediated disorders, daclizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZINBRYTA REMS Program.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: [US Boxed Warning]: Daclizumab may cause severe hepatic injury, including hepatic failure and autoimmune hepatitis; may be life-threatening or fatal. Hepatotoxicity, including autoimmune hepatitis, may occur at any time during daclizumab treatment; cases have been reported up to 4 months after the last dose. Daclizumab is contraindicated in patients with preexisting hepatic disease or hepatic impairment. Obtain serum transaminases (ALT and AST) and total bilirubin levels prior to treatment initiation, monthly before each dose, and monthly for 6 months after the last daclizumab dose. If transaminases or total bilirubin are elevated, treatment interruption or discontinuation may be required. Some patients required systemic corticosteroids or other immunosuppressant treatment for autoimmune hepatitis and continued this treatment after the last daclizumab dose. ALT or AST elevations (including rare elevations >20 times ULN) and bilirubin elevations have occurred during treatment and up to 4 months following the last dose. Monitor for clinical signs/symptoms of hepatic dysfunction (unexplained nausea, vomiting, abdominal pain, anorexia, fatigue, jaundice, and/or dark urine); if reported, promptly obtain serum transaminases and total bilirubin; may require treatment interruption or discontinuation. Prolonged transaminase elevations should be evaluated for alternate causes, including infection. If autoimmune hepatitis is suspected, promptly discontinue daclizumab; may require systemic corticosteroids and other immunosuppressant therapy. Long-term immunosuppression may be necessary. The use of other medications (including OTC medications) associated with hepatotoxicity should be used with caution in combination with daclizumab; carefully consider the need for herbal medicine and dietary supplements which may cause hepatotoxicity.

• Hypersensitivity: Daclizumab may cause anaphylaxis, angioedema, and urticaria after the first dose or at any time during treatment. If anaphylaxis or other allergic reaction occurs, discontinue daclizumab and do not re-initiate.

• Immune-mediated disorders: [US Boxed Warning]: In addition to autoimmune hepatitis, other immune-mediated disorders such as skin reactions, lymphadenopathy, and noninfectious colitis, may occur with daclizumab. Serious immune-mediated conditions were observed in patients who received daclizumab. If a serious immune-mediated disorder develops, consider stopping daclizumab and refer to a specialist for a comprehensive diagnostic evaluation and appropriate management. Some patients required systemic corticosteroids or other immunosuppressant treatment for immune-mediated disorders and continued this treatment after the last daclizumab dose. Concurrent or sequential immune-mediated disorders have been reported during daclizumab treatment. Immune-mediated disorders have resulted in invasive diagnostic procedures, hospitalization, and/or prolonged systemic corticosteroids or other immunosuppressant therapy; some events had not resolved following daclizumab discontinuation and follow-up. Immune- mediated disorders have involved a single organ, or systemic multi-organ reactions. Monitor closely for immune-mediated disorders. Suspected immune-mediated disorders should be adequately evaluated to confirm etiology or to exclude other causes. For serious immune-mediated disorders, consider discontinuing treatment and referring to appropriate specialist for further evaluation and management. Some immune-mediated disorders have required several months for resolution.

• Dermatologic toxicity: Immune-mediated skin reactions, including rash, dermatitis, eczema, and psoriatic conditions, have occurred with daclizumab; may occur at any time during therapy. Photosensitivity has also been reported. Daclizumab may exacerbate eczema or psoriasis in patients with a history of those conditions. Dermatologic toxicity may be managed with topical or systemic corticosteroids, or immunosuppressant therapy (eg, tacrolimus). Some skin reactions have required discontinuation. Rash typically resolved at ~3 months, although some rashes remained unresolved at the final clinical evaluation. Infectious complications due to serious cutaneous reaction has been reported, including a rare fatality. Serious diffuse or inflammatory rashes should be evaluated by a dermatologist prior to the next dose; discontinuation may be appropriate.

• Gastrointestinal toxicity: Serious non-infectious colitis was reported in patients receiving daclizumab. If symptoms of colitis (abdominal pain, fever, prolonged diarrhea) occur, consider referring to a gastroenterologist.

• Lymphadenopathy: An increased incidence of lymphadenopathy was reported in patients who received daclizumab. The onset of lymphadenopathy may occur throughout the daclizumab treatment period. Serious events related to lymphadenopathy/lymphadenitis included infections, salivary neoplasm (benign), skin reactions, thrombocytopenia, and interstitial lung changes. Most cases resolved within 3 months, either with treatment continuing or discontinued. If lymph node biopsy is considered, the patient should undergo a full diagnostic exam by a specialist.

• Infection: Daclizumab increases the risk for infections (some serious). Upper respiratory tract infections, urinary tract infections and viral infections were the most common infections. Avoid initiating daclizumab in patients with severe active infection. If serious infection develops while on therapy, consider withholding daclizumab until infection resolves. Screen for hepatitis B and C prior to treatment initiation.

• Neuropsychiatric events: Depression-related events occurred more frequently in patients receiving daclizumab than in patients who received placebo or comparator drug. Some events were serious, including suicidal ideation or attempt. Use daclizumab with caution in patients with prior or current depressive disorders. Patients or caregivers should immediately report symptoms of new or worsening depression or suicidal ideation. Consider discontinuing daclizumab if severe depression or suicidal ideation develops.

• Tuberculosis: In countries where tuberculosis is endemic, cases of tuberculosis occurred in patients receiving daclizumab. Evaluate patients at high risk for tuberculosis infection prior to treatment initiation. If a test is positive, treat tuberculosis (with standard medical therapy) prior to daclizumab treatment. Avoid initiating daclizumab in patients with tuberculosis.

Disease related concerns:

• Hepatic disease: Patients with ALT or AST >2 times ULN were excluded from clinical studies. Patients with signs/symptoms of hepatic impairment may be at increased risk for hepatotoxicity. Use is contraindicated in patients with preexisting hepatic disease, hepatic impairment, or history of autoimmune hepatitis (or other autoimmune condition involving the liver).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatrics: Due to the risk of hepatic injury and immune-mediated disorders, the use of daclizumab is not recommended in patients <17 years of age.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002, Lucente 2000, Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986, CDC 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Immunizations: Immunization with live vaccines is not recommended during treatment and for up to 4 months after discontinuation. Consider necessary immunization prior to initiation of daclizumab treatment.

• Immunogenicity: Anti-daclizumab antibodies and neutralizing antibodies may develop, usually during the first year of treatment, with the frequency declining with continued treatment. Anti-daclizumab antibodies were transient in some patients and persistent in others. Daclizumab clearance was increased in patients who developed neutralizing antibodies. Anti-daclizumab antibody and neutralizing antibody development did not correlate to clinical response, adverse reactions, or pharmacodynamics.

• REMS program: [US Boxed Warning]: Due to the risks of hepatotoxicity (including autoimmune hepatitis) and other immune-mediated disorders, daclizumab is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZINBRYTA REMS Program. Prescribers and pharmacies must be certified with the program and patients must be enrolled in the program and comply with ongoing monitoring requirements. Further information is available at 1-800-456-2255.

Monitoring Parameters

ALT, AST, and total bilirubin (prior to treatment, then monthly during treatment [prior to the next dose] and for 6 months after the last dose). Evaluate for tuberculosis (in patients at high risk) prior to treatment. Evaluate immunization status prior to treatment. Monitor for signs/symptoms of colitis, depression, dermatologic toxicity, hepatic dysfunction, hypersensitivity, immune-mediated disorders, and infection.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Daclizumab is a monoclonal antibody; monoclonal antibodies are known to cross the placenta, with increasing amounts during the second and third trimesters. Use of similar agents is not recommended for the treatment of multiple sclerosis in pregnant women (Coyle 2016, Pozzilli 2015).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pharyngitis, rhinitis, signs of common cold, or flu-like symptoms. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), skin reaction, skin irritation, swollen glands, bloody stools, severe diarrhea, abdominal pain, signs of infection, or signs of depression (suicidal ideation, anxiety, emotional instability, or confusion) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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