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Zinbryta

Generic Name: Daclizumab
Class: Immunomodulatory Agents
Chemical Name: Humanized anti-TAC monoclonal antibody comprised of four subunits, two heavy chains and two light chains. All four chains are linked via disulfide bridges. The molecule contains approximately 2% carbohydrate by weight. The antibody belongs to the IgG1 subclass. The DNA sequence is 90% human origin and 10% mouse origin. The humanized anti-TAC is directed to the TAC receptor or high-affinity interleukin 2 receptor. Immunoglobulin G1 (human-mouse monoclonal clone 1H4 γ-chain anti-human interleukin 2 receptor), disulfide with human-mouse monoclonal clone 1H4 light chain, dimer. Molecular weight is approximately 150,000 daltons.
Molecular Formula: C6394H9888N1696O2012S44
CAS Number: 152923-56-3

Warning(s)

    Hepatic Injury Including Autoimmune Hepatitis
  • Risk of severe, potentially life-threatening hepatic injury, including liver failure and autoimmune hepatitis.1 (See Hepatic Injury under Cautions.)

  • Contraindicated in patients with preexisting hepatic disease or hepatic impairment.1 (See Contraindications under Cautions.)

  • Evaluate serum aminotransferase and total bilirubin concentrations prior to initiation of therapy and monthly prior to each dose of the drug.1

  • Interruption or discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

    Other Immune-mediated Disorders
  • Other immune-mediated adverse reactions reported (e.g., skin reactions, lymphadenopathy, noninfectious colitis).1 (See Other Immune-mediated Disorders under Cautions.)

  • If a serious immune-mediated disorder develops, consider interruption of daclizumab therapy and refer patient to a specialist for evaluation and treatment.1

REMS:

FDA approved a REMS for daclizumab to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of daclizumab and consists of the following: communication plan, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). (Also see Restricted Distribution Program under Dosage and Administration.)

Introduction

Immunomodulatory agent; a humanized anti-interleukin-2 (IL-2) receptor monoclonal antibody.1 2 3 13 14 15

Uses for Zinbryta

Multiple Sclerosis

Management of relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).1 2 3 23 24

Because of potentially life-threatening adverse effects (e.g., hepatotoxicity, immune-mediated disorders), generally reserved for patients with inadequate response to ≥2 MS drugs.1 (See Cautions.)

Other Uses

Has been used in conjunction with immunosuppressive agents (cyclosporine and corticosteroids) for prevention of acute organ rejection in patients receiving renal transplants.4 21 Previously available as an IV formulation (Zenapax) for this use, but withdrawn from US market in 2009 for reasons other than safety or effectiveness.4 22

Zinbryta Dosage and Administration

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

Multiple Sclerosis
Sub-Q

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

Dosage Modification for Toxicity
Hepatic Toxicity

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

Cautions for Zinbryta

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

Hepatic Injury

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

Other Immune-mediated Disorders

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

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

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

Noninfectious Colitis

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

Hypersensitivity Reactions

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.)

Infectious Complications

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 and Suicide

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

Immunogenicity

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

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

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

Interactions for Zinbryta

Not expected to undergo metabolism by CYP isoenzymes; therefore, clinically important pharmacokinetic interactions with CYP inhibitors and inducers unlikely.1 4 5

Does not appear to affect CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A.1 5 28 Dosage adjustment of drugs metabolized by these CYP isoenzymes is not necessary.4

Hepatotoxic Drugs

Potential increased risk of hepatotoxicity when used with other hepatotoxic drugs, including prescription and OTC drugs and dietary or herbal supplements; use concomitantly with caution.1

Vaccines

Do not administer live vaccines during therapy and for up to 4 months following discontinuance of the drug.1

Specific Drugs

Drug

Interaction

Comments

Caffeine

No clinically important effect on systemic exposure of caffeine 1 5

Dextromethorphan

No clinically important effect on systemic exposure of dextromethorphan1 5

Dosage adjustment of dextromethorphan not necessary4

Midazolam, oral

No clinically important effect on systemic exposure of midazolam1 5

Dosage adjustment of midazolam not necessary4

Omeprazole

No clinically important effect on systemic exposure of omeprazole1 5

Dosage adjustment of omeprazole not necessary4

Warfarin

No clinically important effect on systemic exposure of warfarin 1 5

Dosage adjustment of warfarin not necessary4

Zinbryta Pharmacokinetics

Absorption

Bioavailability

Absolute sub-Q bioavailability approximately 90%.1 5 Peak serum concentration occurs in 5–7 days following sub-Q administration.1 5 10

Steady-state concentrations achieved by the fourth dose following monthly administration; systemic accumulation of the drug is 2.5-fold.1 10

Special Populations

Similar pharmacokinetics in healthy individuals and patients with MS.1 5 14

Age, gender, race, or body weight does not appear to affect pharmacokinetics.1 5

Distribution

Extent

Distributed into milk in monkeys; not known whether distributed into human milk.1

Elimination

Elimination Route

Presumed to be catabolized into peptides and amino acids in the same manner as endogenous IgG.1

Half-life

Approximately 21 days.1

Special Populations

Clearance is 19% higher in patients who develop neutralizing antibodies to the drug.1

Stability

Storage

Parenteral

Injection

2–8°C in original carton to protect from light.1 Do not expose to temperatures >30°C.1 Do not freeze; discard if accidentally frozen.1

May be stored at temperatures up to 30°C for up to 30 days if refrigeration unavailable; do not return to refrigerator after allowing drug to warm to room temperature.1

Actions

  • Humanized monoclonal antibody that binds specifically to the α subunit (CD25) of the high-affinity IL-2 receptor.1 2 3 13 14 15

  • Although exact mechanism in MS not fully elucidated, presumed to involve modulation of IL-2-mediated activation of lymphocytes through binding of daclizumab to CD25.1 13 14 15 17

  • In addition to direct inhibitory effects on CD25-expressing activated T cells, appears to exert a variety of other immunologic effects including the expansion of immunoregulatory CD56bright natural killer (NK) cells.2 3 12 13 14 15 17 18 19 20

  • An increase in CD56bright NK cells has been associated with a reduction in brain inflammatory activity (i.e., fewer new or newly enlarging T2-hyperintense lesions) in patients with MS.3 13 14 15 16 17

  • Other clinically important immunologic effects include inhibition of antigen-specific T-cell activation by dendritic cells and a reduction in proinflammatory lymphoid-tissue inducer cells.2 3 13 14 15 17 18 19 20

Advice to Patients

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of daclizumab is restricted.1 8 (See Restricted Distribution Program under Dosage and Administration.)

Daclizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

150 mg/mL

Zinbryta (available as 1-mL single-dose prefilled syringes)

Biogen

AHFS DI Essentials. © Copyright 2017, Selected Revisions March 9, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Biogen, Inc. Zinbryta (daclizumab) injection, for subcutaneous use prescribing information. Cambridge, MA; 2016 May.

2. Kappos L, Wiendl H, Selmaj K et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2015; 373:1418-28. [PubMed 26444729]

3. Gold R, Giovannoni G, Selmaj K et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013; 381:2167-75. [PubMed 23562009]

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761029Orig1s000: Summary Review.. From FDA website.

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761029Orig1s000: Clinical Pharmacology and Biopharmaceutics Review(s). From FDA website.

6. Biogen, Inc. Zinbryta (daclizumab) injection, for subcutaneous use medication guide. Cambridge, MA; 2016 May.

7. Biogen, Inc. Zinbryta (daclizumab) injection, for subcutaneous use instructions for use. Cambridge, MA; 2016 May.

8. Biogen and AbbVie, Inc. Zinbryta REMS (Risk Evaluation and Mitigation Strategy) program overview. Research Triangle Park, NC; 2016 May.

9. Gold R, Stefoski D, Selmaj K et al. Pregnancy Experience: Nonclinical Studies and Pregnancy Outcomes in the Daclizumab Clinical Study Program. Neurol Ther. 2016; :. [PubMed 27411694]

10. Tran JQ, Othman AA, Mikulskis A et al. Pharmacokinetics of daclizumab high-yield process with repeated administration of the clinical subcutaneous regimen in patients with relapsing-remitting multiple sclerosis. Clin Pharmacol. 2016; 8:9-13. [PubMed 26929672]

11. Krueger JG, Kircik L, Hougeir F et al. Cutaneous Adverse Events in the Randomized, Double-Blind, Active-Comparator DECIDE Study of Daclizumab High-Yield Process Versus Intramuscular Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis. Adv Ther. 2016; 33:1231-45. [PubMed 27251051]

12. Lin YC, Winokur P, Blake A et al. Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination. Neurol Neuroimmunol Neuroinflamm. 2016; 3:e196. [PubMed 26848487]

13. Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics. 2013; 10:55-67. [PubMed 23055048]

14. Cohan S. Therapeutic efficacy of monthly subcutaneous injection of daclizumab in relapsing multiple sclerosis. Biologics. 2016; 10:119-38. [PubMed 27672308]

15. Elkins J, Sheridan J, Amaravadi L et al. CD56(bright) natural killer cells and response to daclizumab HYP in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm. 2015; 2:e65. [PubMed 25635261]

16. Jiang W, Chai NR, Maric D et al. Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis. J Immunol. 2011; 187:781-90. [PubMed 21666061]

17. Bielekova B, Catalfamo M, Reichert-Scrivner S et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A. 2006; 103:5941-6. [PubMed 16585503]

18. Lin YC, Winokur P, Blake A et al. Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis. Ann Clin Transl Neurol. 2015; 2:445-55. [PubMed 26000318]

19. Wuest SC, Edwan JH, Martin JF et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med. 2011; 17:604-9. [PubMed 21532597]

20. Perry JS, Han S, Xu Q et al. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci Transl Med. 2012; 4:145ra106. [PubMed 22855463]

21. Roche Laboratories Inc. Zenapax (daclizumab) sterile concentrate for injection prescribing information. Nutley, NJ: 2005 Sep.

22. Birgerson L. Dear healthcare professional letter regarding discontinuation of Zenapax. Nutley, NJ: Hoffmann-La Roche, Inc.; 2009 Sep.

23. Giovannoni G, Gold R, Selmaj K et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol. 2014; 13:472-81. [PubMed 24656609]

24. Gold R, Radue EW, Giovannoni G et al. Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study. BMC Neurol. 2016; 16:117. [PubMed 27461166]

25. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761029Orig1s000: Summary Review.. From FDA website.

26. Cortese I, Ohayon J, Fenton K et al. Cutaneous adverse events in multiple sclerosis patients treated with daclizumab. Neurology. 2016; 86:847-55. [PubMed 26843560]

27. Krueger JG, Kircik L, Hougeir F et al. Cutaneous Adverse Events in the Randomized, Double-Blind, Active-Comparator DECIDE Study of Daclizumab High-Yield Process Versus Intramuscular Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis. Adv Ther. 2016; 33:1231-45. [PubMed 27251051]

28. Tran JQ, Othman AA, Wolstencroft P et al. Therapeutic protein-drug interaction assessment for daclizumab high-yield process in patients with multiple sclerosis using a cocktail approach. Br J Clin Pharmacol. 2016; 82:160-7. [PubMed 26991517]

29. Minocha M, Tran JQ, Sheridan JP et al. Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials. Clin Pharmacokinet. 2016; 55:121-30. [PubMed 26242380]

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