Zenapax

Generic Name: Daclizumab
Class: Immunosuppressive Agents
VA Class: IM600
Molecular Formula: C6394H9888N1696O2012S44
CAS Number: 152923-56-3

Warning(s)

  • Only clinicians experienced in immunosuppressive therapy and the management of organ transplant patients should prescribe daclizumab.1

  • The clinician responsible for the administration of daclizumab should have complete information necessary for follow-up of the patient.1

  • Daclizumab should only be administered by medical personnel trained in administration of the drug who have adequate laboratory and supportive medical resources.1

Introduction

Immunosuppressive agent; recombinant anti-CD25 immunoglobulin G1 (IgG1) monoclonal antibody.1 3 4 5 6 7 9 10 11 12 13 14 15

Uses for Zenapax

Renal Allotransplantation

Prevention of acute rejection of renal allografts in adults and children 11 months to 17 years of age.1 3 4 5 6 7 9 10 11 12 13 14 15

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Designated an orphan drug by FDA for this use.2

Manufacturer recommends use in conjunction with cyclosporine and corticosteroids.1 3 4 5 6 11 12 15

Efficacy in preventing acute rejection in recipients of other solid organ transplants has not been demonstrated.1

Zenapax Dosage and Administration

Administration

IV Infusion

Administer by IV infusion, either via a peripheral or central vein.1 3 4 5 6 7 9 10 11 12 13 14 15

Administer in conjunction with cyclosporine and corticosteroid therapy.1 3 4 5 6 7 9 10 11 12 13 14 15

Dilution

Must be diluted prior to administration; do notadminister concentrate for injection undiluted.1

Dilute appropriate dose of the concentrate for injection (containing 5 mg/mL) in 50 mL of 0.9% sodium chloride injection.1

Gently invert the IV bag to mix the solution, but do not shake.1

Rate of Administration

Infuse the appropriate dose over 15 minutes.1 3 4 15

Dosage

Pediatric Patients

Renal Allotransplantation
Prevention of Allograft Rejection
IV Infusion

Children 11 months to 17 years of age: 5 doses, 1 mg/kg each.1 3 4

First dose given within 24 hours prior to transplantation, remaining 4 doses (doses 2–5) at 14-day intervals.1 3 4

Adults

Renal Allotransplantation
Prevention of Allograft Rejection
IV Infusion

5 doses, 1 mg/kg each.1 3 4

First dose given within 24 hours prior to transplantation, remaining 4 doses (doses 2–5) at 14-day intervals.1 3 4

Prescribing Limits

Pediatric Patients

Renal Allotransplantation
IV Infusion

Maximum of 5 doses; minimum 14-day interval between doses.1

Adults

Renal Allotransplantation
IV Infusion

Maximum of 5 doses; minimum 14-day interval between doses.1

Special Populations

Renal Impairment

Dosage adjustment is not required in severe renal impairment.1

Geriatric Patients

Dosage adjustment is not required for geriatric patients; in general, use immunosupressive agents with caution.1

Cautions for Zenapax

Contraindications

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

Warnings/Precautions

Warnings

For warnings regarding supervising clinicians, see Boxed Warning.

Increased Mortality in Cardiac Allograft

Increased mortality reported when daclizumab (in conjunction with a standard immunosuppressive regimen containing cyclosporine, mycophenolate mofetil, and corticosteroids) used to prevent rejection after cardiac transplant; some deaths were associated with severe infections.1 18

Concomitant use of anti-lymphocyte antibody therapy also may be associated with the fatal infections.1 18

Lymphoproliferative Disorders and Opportunistic Infections

Monitor patients for lymphoproliferative disorders and/or opportunistic infections; risk is increased with immunosuppressive therapy;1 3 5 6 11 13 14 15 incidence with daclizumab similar to that with placebo.1 3 5 6 11 13 14 15

Sensitivity Reactions

Severe, acute (onset within 24 hours) hypersensitivity reactions, including anaphylaxis, have occurred after initial daclizumab exposure and subsequent reexposure.1 18

Drugs to treat severe hypersensitivity reactions, including anaphylaxis, should be immediately available.1 18

If hypersensitivity reaction occurs, immediately discontinue daclizumab permanently and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway and oxygen).1 18

In patients who have previously received the drug, a subsequent course of therapy with daclizumab should be given with caution.1 18

Report any serious adverse effect associated with daclizumab to the manufacturer by phone (800-526-6367) or to the FDA Medwatch program by phone (800-FDA-1088) or by fax (800-FDA-0178), or by internet () or by mail (using postage paid FDA-3500 form) to Medwatch, 5600 Fishers Lane, Rockville, MD 20852-9787.18

General Precautions

Immune Response

Long-term effect on immune system's ability to respond to antigens first encountered during daclizumab-induced immunosuppression is not known.1

Daclizumab Readministration

Not systematically studied.1 18 The potential risks (e.g., immunosuppression-associated risks, anaphylactic/anaphylactoid reactions) to previously treated patients are not known.1

Specific Populations

Pregnancy

Category C.1

Manufacturer recommends use of effective contraception before, during, and for 4 months following daclizumab use in women of childbearing potential.1

Lactation

Not known whether daclizumab is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <11 months of age.1

Safety and efficacy in children 11 months to 17 years of age for prevention of renal allograft rejection is supported by evidence from adult studies and data from a pediatric pharmacokinetic study.1 3 4 5 6 8 11 12 14

Not known whether immune response to vaccines, infections, or other antigens is impaired during or will remain impaired after daclizumab therapy.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; administer immunosuppressive drugs with caution.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment.1

Common Adverse Effects

Constipation,1 nausea,1 diarrhea,1 vomiting,1 abdominal pain,1 pyrosis,1 dyspepsia,1 abdominal distention,1 and epigastric pain (not food-related);1 incidence similar to placebo.1

Interactions for Zenapax

Specific Drugs

Drug

Interaction

Comments

Acyclovir

No increase in adverse effects observed with concomitant daclizumab, immunosuppressant, anti-infective, and/or corticosteroid therapy1 11 12

Antilymphocyte globulin (ALG)

Increased mortality, particularly with concomitant anti-lymphocyte antibody therapy, reported in regimen of daclizumab, cyclosporine, mycophenolate mofetil, and corticosteroids to prevent cardiac transplant rejection1 18

Limited experience with other regimens1

Antithymocyte globulin (ATG)

Limited experience1

Azathioprine

No increase in adverse effects observed with concomitant daclizumab, immunosuppressant, anti-infective, and/or corticosteroid therapy1 11 12

Corticosteroids

Increased mortality reported in regimen of cyclosporine, mycophenolate mofetil, and corticosteroids to prevent cardiac transplant rejection, particularly with concomitant anti-lymphocyte antibody therapy1 18

No increase in adverse effects observed with concomitant daclizumab, immunosuppressant, or anti-infective therapy1 11 12

Cyclosporine

Increased mortality reported in regimen of cyclosporine, mycophenolate mofetil, and corticosteroids to prevent cardiac transplant rejection, particularly with concomitant anti-lymphocyte antibody therapy1 18

No increase in adverse effects observed with concomitant daclizumab, immunosuppressant, anti-infective, and/or corticosteroid therapy1 11 12

Ganciclovir

No increase in adverse effects observed with concomitant daclizumab, immunosuppressant, anti-infective, and/or corticosteroid therapy1 11 12

Muromonab-CD3 (OKT3)

Limited experience1

Mycophenolate mofetil

Increased mortality reported in regimen of cyclosporine, mycophenolate mofetil, and corticosteroids to prevent cardiac transplant rejection, particularly with concomitant anti-lymphocyte antibody therapy1 18

No increase in adverse effects observed with concomitant daclizumab, immunosuppressant, anti-infective, and/or corticosteroid therapy1 11 12

Tacrolimus

Limited experience1

Zenapax Pharmacokinetics

Absorption

Duration

Duration of clinically important IL-2 receptor blockade is unknown.1

With recommended regimen, saturation of IL-2 receptor TAC subunit after transplantation is 90 days in children, 120 days in adults.1

Distribution

Extent

Generally, immune globulin molecules cross the placenta, but not known whether daclizumab does; not known if daclizumab is distributed into milk.1

Elimination

Half-life

11–38 days.1

Stability

Storage

Parenteral

For Injection, concentrate, for IV Infusion

2–8°C; do not freeze.1

Do not shake; protect from direct light.1

Store diluted solutions at room temperature, use within 4 hours of preparation.1

Alternatively, diluted solutions may be stored at 2–8°C for up to 24 hours after preparation.1 17

Discard unused diluted solutions within 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Incompatibility not observed with polyvinyl chloride or polyethylene bags or infusion sets.1

Drug Compatibility

Unknown whether daclizumab is compatible with other IV drugs.1

Do not admix with other drugs; do not infuse other drugs simultaneously through the same IV line.1

Actions

  • Recombinant DNA-derived humanized (human-murine) anti-CD25 monoclonal immunoglobulin G1 (IgG1) antibody immunosuppressant agent.1 3 4 5 6 7 9 10 11 12 13 14 15

  • Competitively inhibits IL-2-mediated lymphocyte activation integral to cell-mediated immune response involved in allograft rejection.1 3 14

  • Exact mechanism of the immunosuppressive effect not fully elucidated; apparently binds with high affinity to the α chain of the interleukin-2 receptor (IL-2Rα) (i.e., T-cell activation antigen [TAC], CD25 antigen)1 3 4 5 6 7 9 12 15 and inhibits binding of IL-2 to antigenically stimulated T lymphocytes (resting lymphocytes are not affected).1 3 5 9 10 13

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.1

  • Importance of informing patients about the potential benefits of daclizumab and attendant risks of immunosuppressive therapy.1

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

Preparations

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

Daclizumab (Recombinant DNA)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion

5 mg/mL (25 mg)

Zenapax

Roche

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2004. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Roche Laboratories Inc. Zenapax (daclizumab) sterile concentrate for injection prescribing information. Nutley, NJ: 2003 July.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD; 2001 May. From FDA web site accessed April 4, 2003. ().

3. Vincenti F, Kirkman R, Light S et al for the Daclizumab Triple Therapy Study Group. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med. 1998; 338:161-5. [IDIS 400212] [PubMed 9428817]

4. Nashan B, Light S, Hardie IR et al for the Daclizumab Double Therapy Study Group. Reduction of acute renal allograft rejection by daclizumab. Transplantation. 1999; 67:110-5. [IDIS 421768] [PubMed 9921806]

5. Vincenti F, Nashan B, Light S for the Double Therapy and the Triple Therapy Study Groups. Daclizumab: Outcome of phase III trials and mechanism of action. Transplant Proc. 1998; 30:2155-8. [IDIS 413384] [PubMed 9723424]

6. Bumgardner GL, Hardie I, Johnson RW et al for the Phase III Daclizumab Study Group. Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation. Transplantation. 2001; 72:839-45. [IDIS 469559] [PubMed 11571447]

7. Ettenger RB. New immunosuppressive agents in pediatric renal transplantation. Transplant Proc.1998;30:1956-8.

8. Ettenger RB. Antibody therapy as an induction regimen in pediatric renal transplantation. Transplant Proc. 1999; 31:2677-8. [IDIS 434628] [PubMed 10500765]

9. Vincenti F. Daclizumab: novel biologic immunoprophylaxis for prevention of acute rejection in renal transplantation. Transplant Proc. 1999; 31:2206-7. [IDIS 434583] [PubMed 10500546]

10. Waldmann TA, O’Shea J. The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol. 1998; 10:507-12. [PubMed 9794841]

11. Carswell CI, Plosker GL, Wagstaff AJ. Daclizumab: a review of its use in the management of organ transplantation. BioDrugs. 2001; 15:745-73. [PubMed 11707149]

12. Wiseman LR, Faulds D. Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients. Drugs. 1999; 58:1029-42. [PubMed 10651389]

13. Olyaei AJ, Thi K, deMattos AM et al. Use of basiliximab and daclizumab in kidney transplantation. Prog Transplant. 2001;11:33-7.

14. Berard JL, Velez RL, Freeman RB et al. A review of interleukin-2 receptor antagonists in solid organ transplantation. Pharmacotherapy. 1999; 19:1127-37. [IDIS 434118] [PubMed 10512062]

15. Ekberg H, Backman L, Tufveson G, et al. Daclizumab prevents acute rejection and improves patient survival post transplantation: 1 year pooled analysis. Transpl Int. 2000;13:151-9.

16. Nashan B, Moore R, Amlot P et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet. 1997; 350:1193-8. [IDIS 394766] [PubMed 9652559]

17. Roche Laboratories, Nutley, NY: Personal communication.

18. Gordon RD. Dear doctor letter regarding important drug warning of daclizumab. Nutley, NJ: Roche Laboratories Inc. 2003 Aug.

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