Professional Information
Daclizumab (Systemic)
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VA CLASSIFICATION
Primary: IM403
Commonly used brand name(s): Zenapax.
Another commonly used name is
dacliximab .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Immunosuppressant{01}—
monoclonal antibody{01}—
Indications
General considerations
The efficacy of daclizumab was demonstrated in two placebo-controlled, multicenter trials in which daclizumab was administered in conjunction with triple-therapy (cyclosporine, corticosteroids, and azathioprine) or double-therapy (cyclosporine and corticosteroids) {01}. The primary end point in the trials was the incidence of biopsy-proven acute rejection within the first 6 months following transplantation {01}. The incidence of biopsy-proven acute rejection was lower in the daclizumab-treated group in both the triple-therapy ( P = 0.03) and the double-therapy ( P = 0.001) trials {01}.
A secondary end point in the trials was the incidence of biopsy-proven acute rejection at 1 year following transplantation. Biopsy-proven rejection at 1 year was not significantly different between the placebo-treated group (38%) and the daclizumab-treated group (28%) in the triple-therapy regimen ( P = 0.09) {01}. However, there was a significant difference in this end point in the double-therapy regimen (49% vs 28% incidence of biopsy-proven rejection in the placebo-treated and daclizumab-treated groups, respectively [ P < 0.001]) {01}.
Another secondary end point in the trials was graft survival 1 year following transplantation. There was no significant difference in either the triple-therapy trial ( P = 0.08) or the double-therapy trial ( P = 0.3) {01}.
The trials also compared patient survival at 1 year following transplantation. Patient survival was not significantly different between the placebo-treated group (96%) and the daclizumab-treated group (98%) in the triple-therapy regimen ( P = 0.51) {01}. However, there was a significant difference in this end point in the double-therapy regimen (94% vs 99% survival in the placebo-treated and daclizumab-treated groups, respectively [ P = 0.01]) {01}.
The incidences of lymphoproliferative disorders and opportunistic infections were not increased in the daclizumab-treated patients in the trials {01}. However, only 336 patients were treated with daclizumab in these trials. Additional experience with daclizumab is needed to evaluate its potential for causing lymphoproliferative disorders and opportunistic infections.
The long-term ability of the immune system to respond to antigens first encountered while being treated with daclizumab is not known {01}.
Accepted
Transplant rejection, kidney (prophylaxis)—Daclizumab is indicated, in combination with cyclosporine and corticosteroids, for the prevention of acute rejection of transplanted kidneys {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Composite of human (90%) and murine (10%) antibody sequences obtained through recombinant DNA technology {01}.
Molecular weight—
Approximately 144,000 daltons {01}
pH
Adjusted with hydrochloric acid or sodium hydroxide to approximately 6.9 {01}.
Mechanism of action/Effect:
Daclizumab is an interleukin-2 (IL-2) receptor antagonist that binds to the alpha subunit of IL-2 receptor complex and inhibits IL-2 binding {01}. By inhibiting IL-2 binding, IL-2–mediated activation of lymphocytes is prevented, and the response of the immune system to antigens is impaired {01}.
Distribution:
The volume of distribution (Vol D) is approximately 0.074 L per kg of body weight (L/kg) {01}. The central and peripheral volumes of distribution are estimated to be about 0.031 and 0.0425 L/kg, respectively {01}.
Half-life:
Elimination:
11 to 38 days {01}.
Peak serum concentration:
The peak serum concentration in the five-dose course of treatment occurs after the fifth dose, and is estimated to be 32 ± 22 micrograms per milliliter (mcg/mL) {01}.
Therapeutic serum concentration
5 to 10 mcg/mL {01}.
Precautions to Consider
Carcinogenicity
Studies have not been done to evaluate the carcinogenic potential of daclizumab. In the pre-approval trials of daclizumab, there was not an increased incidence of lymphoproliferative disorders in the daclizumab-treated patients {01}. Long-term follow-up studies are not available in these patients. However, it is known that patients receiving immunosuppressive therapy are at increased risk for developing malignancies.
Mutagenicity
Daclizumab was not mutagenic in the Ames test or the V79 chromosomal aberration assay, with or without activation {01}.
Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies have not been done {01}.
Pregnancy—
Daclizumab crosses the placenta {01}. Adequate and well-controlled studies have not been done in humans {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether daclizumab is distributed into breast milk {01}. The manufacturer recommends that patients receiving daclizumab discontinue breast-feeding {01}.
Pediatrics
Appropriate studies on the relationship of age to the effects of daclizumab have not been performed in pediatric patients {01}. Preliminary data from the use of daclizumab in 25 pediatric patients 11 months to 17 years of age suggest that pediatric patients receiving daclizumab may experience more hypertension and dehydration than adult patients {01}. Although pediatric patients receiving the same weight-adjusted dose as adults (i.e., 1 milligram per kilogram of body weight [mg/kg]) had lower serum concentrations than did adult patients, the dose was sufficient to saturate the alpha subunit of the interleukin-2 (IL-2) receptor on lymphocytes {01}.
Geriatrics
No information is available on the relationship of age to the effects of daclizumab in geriatric patients {01}.
Dental
The immunosuppressive effects of daclizumab may result in an increased incidence of certain microbial infections and delayed healing. Dental work, whenever possible, should be completed prior to initiation of therapy and undertaken with caution during therapy. Patients should be instructed in proper oral hygiene.
Drug interactions and/or related problems
Note: In clinical trials, daclizumab was administered to patients receiving other immunosuppressants (antilymphocyte globulin, antithymocyte globulin, azathioprine, corticosteroids, cyclosporine, muromonab-CD3, mycophenolate mofetil, and tacrolimus) and anti-infectives (acyclovir and ganciclovir). No drug interactions have been evaluated or reported with daclizumab {01}.
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Glucose, blood (concentration may be increased {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Allergy to daclizumab, history of
Note: Anaphylactoid reactions have not been reported following administration of daclizumab {01}. However, anaphylactoid reactions are possible following administration of proteins.
Risk-benefit should be considered when the following medical problems exist
Diabetes mellitus (risk of loss of blood glucose control)
Infection (immunosuppression may exacerbate infection)
Malignancy, current or history of (immunosuppression is associated with an increased incidence of some malignancies )
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Blood pressure and
Heart rate and
Respiratory rate (routine monitoring of vital signs is recommended while daclizumab is administered and for a short period of time following the infusion to monitor for anaphylactoid reaction {01})
Wound infection (daclizumab may cause an increased risk of wound infection {01})
Note: Although the incidences of malignancies and systemic infection were not increased in the daclizumab-treated group in pre-approval clinical trials, patients receiving daclizumab should be monitored routinely for malignancy and systemic infection {01}.
Side/Adverse Effects
Note: In clinical trials, the incidence of adverse effects in the daclizumab-treated group was similar to that in the placebo-treated group {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Chest pain{01}
dyspnea{01} (shortness of breath)
fever{01}
hypertension{01} —usually asymptomatic
hypotension{01} (dizziness)
nausea{01}
peripheral edema{01} (swelling of feet or lower legs)
pulmonary edema{01} (coughing; shortness of breath)
tachycardia{01} (rapid heartbeat)
tremor{01} (trembling or shaking of the hands or feet)
vomiting{01}
weakness{01}
wound infection{01} (red, tender, or oozing skin at incision)
Incidence rare
Hyperglycemia{01} (frequent urination)
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Arthralgia{01} (joint pain)
constipation{01}
diarrhea{01}
dizziness{01}
dyspepsia{01} (heartburn)
headache{01}
insomnia{01} (trouble in sleeping)
myalgia{01} (muscle pain)
slow wound healing{01}
Overdose
There is no clinical experience with overdose of daclizumab, and a maximum tolerated dose has not been established. Some bone marrow transplant recipients have received 1.5 mg per kg of body weight without any adverse effects {01}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Daclizumab— (Systemic) .
In providing consultation, consider emphasizing the following» selected information ( = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Allergy to daclizumab
Carcinogenicity—
Use of daclizumab may be associated with an increased risk of malignancy
Pregnancy—Daclizumab crosses the placenta
Breast-feeding—Use is not recommended
Use in children—Children receiving daclizumab may experience higher incidences of hypertension and dehydration than adult patients
Dental—Dental work should be completed prior to initiation of therapy whenever possible
Proper use of this medication
Proper dosing
Advisability of women of childbearing age using effective contraception before, during, and for several months after receiving daclizumab
Precautions while receiving this medication
» Importance of close monitoring by a physician
Side/adverse effects
Signs of potential side effects, especially chest pain, dyspnea, fever, hypertension, hypotension, nausea, peripheral edema, pulmonary edema, tachycardia, tremor, vomiting, weakness, wound infection and hyperglycemia
General Dosing Information
Daclizumab should be used only by physicians experienced in the management of organ transplant patients {01}. Medications for the treatment of severe hypersensitivity reactions should be immediately available when daclizumab is administered {01}.
Daclizumab must be diluted prior to administration {01}.
Shaking of the vial or prepared solution of daclizumab may cause foaming and should be avoided {01}.
No dosage adjustment is needed for administration to patients with renal function impairment {01}. There are no data for administration to patients with hepatic function impairment {01}.
There is no experience with treating patients with more than one course of therapy with daclizumab {01}.
Parenteral Dosage Forms
DACLIZUMAB STERILE CONCENTRATE FOR INJECTION
Usual adult and adolescent dose
Transplant rejection, kidney (prophylaxis)
Intravenous infusion over fifteen minutes, 1 mg per kg of body weight every fourteen days for five doses beginning no earlier than twenty-four hours prior to transplantation {01}.
Usual pediatric dose
See Usual adult and adolescent dose .
Note: Although testing has not been completed in pediatric patients, preliminary data suggest that the same weight-adjusted dose used in adults is appropriate for pediatric patients {01}.
Usual geriatric dose
See Usual adult and adolescent dose .
Strength(s) usually available
U.S.—
5 mg per mL (Rx) [Zenapax{01} (sodium phosphate monobasic monohydrate 3.6 mg per mL) (sodium phosphate dibasic heptahydrate 11 mg per mL) (sodium chloride 4.6 mg per mL) (polysorbate 80 0.2 mg per mL)]
Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF). Protect from light and freezing.
Preparation of dosage form:
Daclizumab must be diluted prior to infusion. The dose may be diluted in 50 mL of 0.9% sodium chloride injection. When the diluted solution is mixed, the bag should be gently inverted. Care should be taken to avoid shaking vials and prepared solutions of daclizumab. {01}
Stability:
Daclizumab does not contain preservatives. Prepared solutions of daclizumab should be used within 4 hours. If refrigerated at 4 ºC (39 ºF), solutions should be used within 24 hours. The prepared solution should be inspected for particulate matter and clarity before administration to the patient, and should be discarded if particulate matter is present. {01}
Incompatibilities:
There are no data on the compatibility or incompatibility of other drugs or solutions with daclizumab. Until more data are available, other drugs should not be infused simultaneously through the same intravenous line {01}.
Developed: 04/03/1998
References
- Daclizumab package insert (Hoffman-La Roche—US), New 12/97, Rec 12/22/97.
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