ZENAPAX®
(Daclizumab)
STERILE CONCENTRATE FOR INJECTION
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WARNING: Only physicians
experienced in immunosuppressive therapy and management of organ transplant
patients should prescribe ZENAPAX® (Daclizumab). The physician
responsible for ZENAPAX administration should have complete information
requisite for the follow-up of the patient. ZENAPAX should only be
administered by healthcare personnel trained in the administration of the
drug who have available adequate laboratory and supportive medical resources. |
DESCRIPTION:
ZENAPAX® (Daclizumab) is an immunosuppressive, humanized IgG1
monoclonal antibody produced by recombinant DNA technology that binds
specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the
human high-affinity interleukin-2 (IL-2) receptor that is expressed on the
surface of activated lymphocytes.
Daclizumab is a composite of human (90%) and murine (10%) antibody
sequences. The human sequences were derived from the constant domains of human
IgG1 and the variable framework regions of the Eu myeloma antibody. The murine
sequences were derived from the complementarity-determining regions of a murine
anti-Tac antibody. The molecular weight predicted from DNA sequencing is 144
kilodaltons.
ZENAPAX 25 mg/5mL is supplied as a clear, sterile, colorless
concentrate for further dilution and intravenous administration. Each
milliliter of ZENAPAX contains 5 mg of Daclizumab and 3.6 mg sodium phosphate
monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg
sodium chloride, 0.2 mg polysorbate 80 and may contain hydrochloric acid or
sodium hydroxide to adjust the pH to 6.9. No preservatives are added.
CLINICAL
PHARMACOLOGY: Mechanism
of Action: Daclizumab
functions as an IL-2 receptor antagonist that binds with high-affinity to the
Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2
binding. Daclizumab binding is highly specific for Tac, which is expressed on
activated but not resting lymphocytes. Administration of ZENAPAX inhibits
IL-2-mediated activation of lymphocytes, a critical pathway in the cellular
immune response involved in allograft rejection.
While in the circulation, ZENAPAX impairs the response of the
immune system to antigenic challenges. Whether the ability to respond to
repeated or ongoing challenges with those antigens returns to normal after
ZENAPAX is cleared is unknown
(see PRECAUTIONS).
Pharmacokinetics: In clinical trials involving renal allograft patients treated with
a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses, peak
serum concentration (mean ± SD) rose between the first dose (21 ± 14 µg/mL) and
fifth dose (32 ± 22 µg/mL). The mean trough serum concentration before the
fifth dose was 7.6 ± 4.0 µg/mL. In vitro and in vivo data suggest that serum
levels of 5 to 10 µg/mL are necessary for saturation of the Tac subunit of the
IL-2 receptors to block the responses of activated T lymphocytes.
Population pharmacokinetic analysis of the data using a
two-compartment open model gave the following values for a reference patient
(45-year-old male Caucasian patient with a body weight of 80 kg and no
proteinuria): systemic clearance = 15 mL/hour, volume of central compartment =
2.5 liter, volume of peripheral compartment = 3.4 liter. The estimated terminal
elimination half-life for the reference patient was 20 days (480 hours), which
is similar to the terminal elimination half-life for human IgG (18 to 23 days).
Bayesian estimates of terminal elimination half-life ranged from 11 to 38 days for
the 123 patients included in the population analysis.
The influence of body weight on systemic clearance supports the
dosing of ZENAPAX on a milligram per kilogram (mg/kg) basis. For patients
studied, this dosing maintained drug exposure within 30% of the reference
exposure. Covariate analyses showed that no dosage adjustments based on age,
race, gender or degree of proteinuria, are required for renal allograft
patients. The estimated interpatient variability (percent coefficient of
variation) in systemic clearance and central volume of distribution were 15%
and 27%, respectively.
Pharmacodynamics: At the recommended dosage regimen, Daclizu mab saturates the Tac
subunit of the IL-2 receptor for approximately 120 days post-transplant. The
duration of clinically significant IL-2 receptor blockade after the recommended
course of ZENAPAX is not known. No significant changes to circulating
lymphocyte numbers or cell phenotypes were observed by flow cytometry. Cytokine
release syndrome has not been observed after ZENAPAX administration.
CLINICAL
STUDIES: The safety and efficacy of ZENAPAX for the prophylaxis of
acute organ rejection in adult patients receiving their first cadaveric kidney
transplant were assessed in two randomized, double-blind, placebo-controlled,
multicenter trials. These trials compared a dose of 1.0 mg/kg of ZENAPAX with
placebo when each was administered as part of standard immunosuppressive
regimens containing either cyclosporine and corticosteroids (double-therapy
trial, no US sites) or cyclosporine, corticosteroids, and azathioprine
(triple-therapy trial, predominantly US sites) to prevent acute renal allograft
rejection. ZENAPAX dosing was initiated within 24 hours pretransplant, with
subsequent doses given every 14 days for a total of five doses.
The primary efficacy endpoint of both trials was the proportion of
patients who developed a biopsy-proven acute rejection episode within the first
6 months following transplantation. As shown in Table 1, this incidence was
significantly lower in the ZENAPAX-treated group in both the double-therapy and
triple-therapy trials.
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Table 1. Efficacy Parameters |
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No difference in patient survival was observed in the
triple-therapy study between ZENAPAX- and placebo-treated patients. Treatment
with ZENAPAX was associated with better patient survival at 1 year post-transplant
in the double-therapy study.
The incidence of delayed graft function was no different between
placebo-treated and ZENAPAX-treated patients in either study. No difference in
graft function was observed 1 year post-transplant in either study between
placebo-treated and ZENAPAX-treated patients.
In a randomized, double-blind study, ZENAPAX (50 patients) or
placebo (25 patients) was added to an immunosuppressive regimen of
cyclosporine, mycophenolate mofetil, and steroids to assess tolerability,
pharmacokinetics, and drug interactions. The addition of ZENAPAX to an
immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and steroids
did not result in an increased incidence of adverse events or a change in the
types of adverse events reported. The incidence of the combined endpoint of
biopsy-proven or clinically presumptive acute rejection was 20% (5 of 25
patients) in the placebo group and 12% (6 of 50 patients) in the ZENAPAX group.
Although numerically lower, the difference in acute rejection was not
significant.
INDICATION
AND USAGE: ZENAPAX
is indicated for the prophylaxis of acute organ rejection in patients receiving
renal transplants. It is used as part of an immunosuppressive regimen that
includes cyclosporine and corticosteroids.
CONTRAINDICATION: ZENAPAX is
contraindicated in patients with known hypersensitivity to Daclizumab or to any
components of this product.
WARNINGS: See Boxed WARNING.
ZENAPAX should be administered under qualified medical
supervision. Patients should be informed of the potential benefits of therapy
and the risks associated with administration of immunosuppressive therapy.
While the incidence of lymphoproliferative disorders and
opportunistic infections, in the limited clinical trial experience, was no
higher in ZENAPAX-treated patients compared with placebo-treated patients,
patients on immunosuppressive therapy are at increased risk for developing
lymphoproliferative disorders and opportunistic infections and should be
monitored accordingly.
Anaphylactic reactions following administration of proteins can
occur. Severe hypersensitivity reactions following administration of ZENAPAX
have been reported rarely. Therefore, medications for the treatment of severe
hypersensitivity reactions should be available for immediate use.
PRECAUTIONS: General: It is not known whether ZENAPAX use will have a long-term
effect on the ability of the immune system to respond to antigens first encountered
during ZENAPAX-induced immunosuppression.
Re-administration of ZENAPAX after an initial course of therapy
has not been studied in humans. The potential risks of such re-administration,
specifically those associated with immunosuppression and/or the occurrence of
anaphylaxis/anaphylactoid reactions, are not known.
Immunogenicity: Low titers of anti-idiotype antibodies to Daclizumab were detected
in the ZENAPAX-treated patients with an overall incidence of 8.4%. No
antibodies that affected efficacy, safety, serum Daclizumab levels or any other
clinically relevant parameter examined were detected.
Drug Interactions: The following medications have been administered in clinical
trials with ZENAPAX with no incremental increase in adverse reactions: cyclosporine,
mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and
corticosteroids. Very limited experience exists with the use of ZENAPAX
concomitantly with tacrolimus, muromonab-CD3, antithymocyte globulin, and
antilymphocyte globulin.
In renal allograft recipients treated with ZENAPAX and
mycophenolate mofetil, no pharmacokinetic interaction between Daclizumab and
mycophenolic acid, the active metabolite of mycophenolate mofetil, was
observed.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term studies to evaluate
the carcinogenic potential of ZENAPAX have not been performed. ZENAPAX was not
genotoxic in the Ames or the V79 chromosomal aberration assays, with or without
metabolic activation. The effect of ZENAPAX on fertility is not known, because
animal reproduction studies have not been conducted with ZENAPAX (see WARNINGS and ADVERSE
REACTIONS).
Pregnancy: Pregnancy Category C: Animal reproduction studies have not been
conducted with ZENAPAX. Therefore, it is not known whether ZENAPAX can cause
fetal harm when administered to pregnant women or can affect reproductive
capacity. In general, IgG molecules are known to cross the placental barrier.
ZENAPAX should not be used in pregnant women unless the potential benefit
justifies the potential risk to the fetus. Women of childbearing potential
should use effective contraception before beginning ZENAPAX therapy, during
therapy, and for 4 months after completion of ZENAPAX therapy.
Nursing Mothers: It is not known whether ZENAPAX is excreted in human milk. Because
many drugs are excreted in human milk, including human antibodies, and because
of the potential for adverse reactions, a decision should be made to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use: No adequate and well-controlled studies have been completed in
pediatric patients. The preliminary results of an ongoing safety and
pharmacokinetic study (N=25) in pediatric patients (median age: 12 years of
age, range: 11 months to 17 years of age; 11 months to 5 years = 7 patients; 6
years to 12 years = 6 patients; 13 years to 17 years = 12 patients) treated
with ZENAPAX in addition to standard immunosuppressive agents including
mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, and
corticosteroids indicate that the most frequently reported adverse events were
hypertension (48%), post-operative (post-traumatic) pain (44%), diarrhea (36%),
and vomiting (32%). The reported rates of hypertension and dehydration were
higher for pediatric patients than for adult patients. It is not known whether
the immune response to vaccines, infection, and other antigenic stimuli
administered or encountered during ZENAPAX therapy is impaired or whether such
response will remain impaired after ZENAPAX therapy.
The preliminary pharmacokinetic results from this ongoing study in
pediatric patients indicate Daclizumab serum levels (N=6) appear to be somewhat
lower in pediatric renal transplant patients than in adult transplant patients
administered the same dosing regimen. However, Daclizumab levels in these
pediatric patients were sufficient to saturate the Tac subunit of the IL-2
receptor on lymphocytes as measured by flow cytometry (N=24). The Tac subunit
of the IL-2 receptor was saturated immediately after the first dose of 1.0 mg/kg
of Daclizumab and remained saturated for at least the first 3 months
post-transplant. Saturation of the Tac subunit of the IL-2 receptor was similar
to that observed in adult patients receiving the same dose regimen.
Geriatric Use: Clinical studies of ZENAPAX did not include sufficient numbers of
subjects age 65 and older to determine whether they respond differently from
younger subjects. Caution must be used in giving immunosuppressive drugs to
elderly patients.
ADVERSE
REACTIONS: The safety of ZENAPAX was determined in four clinical
studies, three of which were randomized controlled clinical trials, in 629
patients receiving renal allografts of whom 336 received ZENAPAX and 293
received placebo. All patients received concomitant cyclosporine and corticosteroids.
ZENAPAX did not appear to alter the pattern, frequency or severity
of known major toxicities associated with the use of immunosuppressive drugs.
Adverse events were reported by 95% of the patients in the
placebo-treated group and 96% of the patients in the ZENAPAX-treated group. The
proportion of patients prematurely withdrawn from the combined studies because
of adverse events was 8.5% in the placebo-treated group and 8.6% in the
ZENAPAX-treated group.
ZENAPAX did not increase the number of serious adverse events
observed compared with placebo. The most frequently reported adverse events
were gastrointestinal disorders, which were reported with equal frequency in
ZENAPAX- (67%) and placebo-treated (68%) patient groups.
The incidence and types of adverse events were similar in both
placebo-treated and ZENAPAX-treated patients. The following adverse events
occurred in >5% of ZENAPAX-treated patients. These events included: Gastrointestinal
System: constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis,
dyspepsia, abdominal distention, epigastric pain not food-related; Metabolic
and Nutritional: edema extremities, edema; Central and Peripheral
Nervous System: tremor, headache, dizziness; Urinary System:
oliguria, dysuria, renal tubular necrosis; Body as a Whole — General:
post-traumatic pain, chest pain, fever, pain, fatigue; Autonomic Nervous
System: hypertension, hypotension, aggravated hypertension; Respiratory
System: dyspnea, pulmonary edema, coughing; Skin and Appendages: impaired
wound healing without infection, acne; Psychiatric: insomnia; Musculoskeletal
System: musculoskeletal pain, back pain; Heart Rate and Rhythm:
tachycardia; Vascular Extracardiac: thrombosis; Platelet, Bleeding
and Clotting Disorders: bleeding; Hemic and Lymphatic: lymphocele.
The following adverse events occurred in <5% and >2%
of ZENAPAX-treated patients. These included: Gastrointestinal System: flatulence,
gastritis, hemorrhoids; Metabolic and Nutritional: fluid overload, diabetes
mellitus, dehydration; Urinary System: renal damage, hydronephrosis,
urinary tract bleeding, urinary tract disorder, renal insufficiency; Body as
a Whole — General: shivering, generalized weakness; Central and
Peripheral Nervous System: urinary retention, leg cramps, prickly
sensation; Respiratory System: atelectasis, congestion, pharyngitis,
rhinitis, hypoxia, rales, abnormal breath sounds, pleural effusion; Skin and
Appendages: pruritus, hirsutism, rash, night sweats, increased sweating; Psychiatric:
depression, anxiety; Musculoskeletal System: arthralgia, myalgia; Vision:
vision blurred; Application Site: application site reaction.
Incidence of Malignancies: One year after treatment, the incidence of
malignancies was 2.7% in the placebo group compared with 1.5% in the ZENAPAX
group. Addition of ZENAPAX did not increase the number of post-transplant
lymphomas, which occurred with a frequency of <1% in both placebo-treated
and ZENAPAX-treated groups.
Hyperglycemia: No differences in abnormal hematologic or chemical laboratory test
results were seen between placebo-treated and ZENAPAX-treated groups with the
exception of fasting blood glucose. Fasting blood glucose was measured in a
small number of placebo- and ZENAPAX-treated patients. A total of 16% (10 of 64
patients) of placebo-treated and 32% (28 of 88 patients) of ZENAPAX-treated
patients had high fasting blood glucose values. Most of these high values
occurred either on the first day post-transplant when patients received high
doses of corticosteroids or in patients with diabetes.
Incidence of Infectious Episodes: The overall incidence of
infectious episodes, including viral infections, fungal infections, bacteremia
and septicemia, and pneumonia, was not higher in ZENAPAX-treated patients than
in placebo-treated patients. The types of infections reported were similar in
both the ZENAPAX-treated and the placebo-treated groups. Cytomegalovirus
infection was reported in 16% of the patients in the placebo group and 13% of
the patients in the ZENAPAX group. One exception was cellulitis and wound
infections, which occurred in 4.1% of placebo-treated and 8.4% of
ZENAPAX-treated patients. At 1 year post-transplant, 7 placebo patients and
only 1 ZENAPAX-treated patient had died of an infection.
OVERDOSAGE: There have not
been any reports of overdoses with ZENAPAX. A maximum tolerated dose has not
been determined in patients. A dose of 1.5 mg/kg has been administered to bone
marrow transplant recipients without any associated adverse events.
DOSAGE
AND ADMINISTRATION: ZENAPAX is used as part of an immunosuppressive regimen
that includes cyclosporine and corticosteroids. The recommended dose for
ZENAPAX is 1.0 mg/kg. The calculated volume of ZENAPAX should be mixed with 50
mL of sterile 0.9% sodium chloride solution and administered via a peripheral
or central vein over a 15-minute period.
Based on the clinical trials, the standard course of ZENAPAX
therapy is five doses. The first dose should be given no more than 24 hours
before transplantation. The four remaining doses should be given at intervals
of 14 days.
No dosage adjustment is necessary for patients with severe renal
impairment. No dosage adjustments based on other identified covariates (age,
gender, proteinuria, race) are required for renal allograft patients. No data
are available for administration in patients with severe hepatic impairment.
Instructions for Administration:
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ZENAPAX IS NOT FOR DIRECT INJECTION. The calculated volume
should be diluted in 50 mL of sterile 0.9% sodium chloride solution before
intravenous administration to patients. When mixing the solution, gently
invert the bag in order to avoid foaming; DO NOT SHAKE. |
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Parenteral drug products should be inspected visually for particulate
matter and discoloration before administration. If particulate matter is
present or the solution colored, do not use. |
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Care must be taken to assure sterility of the prepared solution,
since the drug product does not contain any antimicrobial preservative or
bacteriostatic agents. |
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ZENAPAX is a colorless solution provided as a single-use vial;
any unused portion of the drug should be discarded. |
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Once the infusion is prepared, it should be administered intravenously
within 4 hours. If it must be held longer, it should be refrigerated between
2° to 8°C (36° to 46°F) for up to 24 hours. After 24 hours, the prepared
solution should be discarded. |
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No incompatibility between ZENAPAX and polyvinyl chloride or
polyethylene bags or infusion sets has been observed. No data are available
concerning the incompatibility of ZENAPAX with other drug substances.
However, other drug substances should not be added or infused simultaneously
through the same intravenous line. |
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ZENAPAX may be administered by healthcare personnel trained in
the administration of the drug who have available adequate laboratory and
supportive medical resources. |
HOW
SUPPLIED: ZENAPAX is supplied in single-use glass vials. Each vial
contains 25 mg of Daclizumab in 5 mL of solution (NDC 0004-0501-09). Vials
should be stored between the temperatures of 2° to 8°C (36° to 46°F); do not
shake or freeze. Protect undiluted solution against direct light. Diluted
medication is stable for 24 hours at 4°C or for 4 hours at room temperature.
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Roche Laboratories Inc., 340 Kingsland Street,
Nutley, New Jersey 07110-1199 |
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US
Govt. Lic. No. 136 |
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