ZINBRYTA

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ZINBRYTA

Classes

Interleukin-2 (IL-2) Inhibitors
MS Agents

Administration

 
NOTE: Daclizumab (Zinbryta) was withdrawn from the worldwide market in March 2018 due to safety concerns. Eight cases of inflammation of the brain, including inflammatory encephalitis and meningoencephalitis, severe hepatic damage, and other immune-mediated disorders were associated with Zinbryta. In the U.S., the use of Zinbryta in multiple sclerosis patients was previously limited to patients who did not respond to prior therapies because of safety concerns associated with use.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Anaphylactic reactions following the administration of daclizumab have been reported. Medications for the treatment of severe hypersensitivity reactions should be available for immediate use during administration of the drug.

Subcutaneous Administration

Prefilled syringes and autoinjectors are for single use only.
Thirty minutes before injection, remove daclizumab from the refrigerator to allow the drug to warm to room temperature. Do not use external heat sources.
Do not place back in the refrigerator after allowing to warm to room temperature.
Daclizumab is a colorless to slightly yellow, clear to slightly opalescent solution. Do not use if the solution is cloudy or there are visible particles.
Wipe injection site with alcohol wipe and allow to dry.
Inject subcutaneously into the thigh, abdomen, or back of the upper arm. Do not inject into skin that is irritated, tender, red, bruised, infected, scarred, or tattooed.
Change injection site for each injection.
If a dose is missed, inject it as soon as possible. If a dose is more than 2 weeks late, skip the missed dose and take the next dose on schedule.
 
Prefilled syringe (Zinbryta)
Firmly hold the needle cover, and pull the needle cover straight off the needle. Do not recap your syringe.
With 1 hand, use thumb and first finger to pinch skin around injection site.
With other hand, use quick, dart-like motion to insert the needle at 90 degrees angle to skin.
Let go of skin, and slowly push plunger down until syringe is empty.
Pull needle straight out of skin.
 
Prefilled autoinjector (Zinbryta)
Do not use if green stripes are not present in the injection status window.
Pull the pen cap straight off. Once the cap is removed, do not recap the pen. This could lock the pen.
Hold pen at 90 degrees to injection site.
Press pen firmly on injection site to begin injection. Continue to hold the pen firmly until clicking sounds stop.
Lift pen from injection site.
Green check marks and yellow plunger should be visible in the injection status window and medication window, respectively, which indicate the full dose has been received.

Adverse Reactions
Severe

new primary malignancy / Delayed / 0-6.5
seizures / Delayed / 1.0-1.0
suicidal ideation / Delayed / 0.4-0.4
anaphylactoid reactions / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatotoxicity / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
erythema nodosum / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
immune-mediated reactions / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known

Moderate

hyperglycemia / Delayed / 32.0-32.0
antibody formation / Delayed / 8.0-19.0
depression / Delayed / 7.0-10.0
elevated hepatic enzymes / Delayed / 0-5.0
lymphadenopathy / Delayed / 5.0-5.0
anemia / Delayed / 3.0-3.0
erythema / Early / 0-2.0
psoriasis / Delayed / 2.0-2.0
colitis / Delayed / 0-1.0
constipation / Delayed / Incidence not known
gastritis / Delayed / Incidence not known
hemorrhoids / Delayed / Incidence not known
dehydration / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
sialadenitis / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
interstitial lung disease / Delayed / Incidence not known
diabetes mellitus / Delayed / Incidence not known

Mild

infection / Delayed / 0-65.0
pharyngitis / Delayed / 6.0-25.0
rash / Early / 7.0-11.0
vesicular rash / Delayed / 7.0-11.0
influenza / Delayed / 9.0-9.0
rhinitis / Early / 4.0-4.0
fever / Early / 3.0-3.0
acne vulgaris / Delayed / 3.0-3.0
diarrhea / Early / 0-2.0
laryngitis / Delayed / 0-2.0
xerosis / Delayed / 0-2.0
pruritus / Rapid / 0-2.0
folliculitis / Delayed / 0-2.0
maculopapular rash / Early / 0-2.0
vomiting / Early / Incidence not known
flatulence / Early / Incidence not known
pyrosis (heartburn) / Early / Incidence not known
nausea / Early / Incidence not known
abdominal pain / Early / Incidence not known

Boxed Warning
Fungal infection, herpes infection, infection, lymphoma, neoplastic disease, requires a specialized care setting, requires an experienced clinician, varicella, viral infection

Daclizumab increases the risk for infections, including tuberculosis. Common types of infections observed during clinical trials of Zinbryta-treated patients were upper respiratory infections, urinary tract infections, and viral infections. Evaluate patients at high risk for tuberculosis infection prior to starting treatment with daclizumab. For patients who test positive for tuberculosis, treat by standard clinical practices prior to starting treatment with daclizumab. Do not initiate daclizumab in a patient with tuberculosis or other severe active infection. If serious infection develops, consider withholding treatment until the infection resolves. The use of daclizumab as part of a multi-drug immunosuppressive regimen in transplant patients may be associated with an increase in severe infections and increased mortality risk. In a randomized trial of daclizumab for the prevention of allograft rejection in cardiac transplant patients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving daclizumab compared to those receiving placebo (7% vs. 5%, respectively, at 6 months; 10% vs. 6%, respectively, at 12 months). Some but not all of the cases appeared to be related to a higher incidence of severe infections. Concomitant use of antilymphocyte antibody therapy may also be a factor in some of the fatal infections. Bacterial, viral, protozoal, and fungal infection occur commonly during immunosuppressive therapy and can be fatal. Reactivation of a latent viral infection, especially herpes infection or varicella, can occur with immunosuppressive therapy. Patients should be instructed to report signs of infection promptly. The incidence of lymphoproliferative disorders and opportunistic infections during clinical trials was no higher in patients treated with daclizumab compared with placebo. Daclizumab therapy requires an experienced clinician; only clinicians experienced in immunosuppressant therapy and organ transplantation and trained in the administration of daclizumab should use daclizumab due to the increased susceptibility to infection and to the possible development of neoplastic disease, especially lymphoma, that may result from immunosuppressive therapy. The clinician responsible for daclizumab administration should have complete information requisite for the follow-up of the patient. Administration of daclizumab to transplant patients requires a specialized care setting equipped and staffed with adequate laboratory and supportive medical services.

Hepatic disease, hepatitis, hepatotoxicity

Daclizumab may cause hepatotoxicity including life-threatening liver failure and autoimmune hepatitis. It is recommended to evaluate transaminase and bilirubin concentrations before initiation of treatment with the Zinbryta formulation and screen patients for hepatitis B and C. Zinbryta is contraindicated in patients with pre-existing hepatic disease or hepatic impairment, including ALT or AST at least 2 times the upper limit of normal (ULN), or a history of autoimmune hepatitis or other autoimmune disease involving the liver. After initiation, obtain transaminase and total bilirubin concentrations monthly for 6 months after the last dose. Treatment modifications are recommended if any of the following liver test abnormalities occur: If ALT or AST more than 5 times ULN, total bilirubin more than 2 times the ULN, or ALT or AST 3 times or more but less than 5 times ULN and total bilirubin more than 1.5 times but less than 2 times ULN. Therapy should be interrupted and alternative etiologies should be investigated. If no other etiologies are found, daclizumab should be discontinued. If other etiologies are identified, re-assess the risks and benefits of therapy. Therapy may be resumed when both AST and ALT are less than 2 times ULN and total bilirubin is at ULN or less. If a patient develops clinical signs or symptoms of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, jaundice and/or dark urine), measure serum transaminases and total bilirubin or discontinue treatment. Discontinue daclizumab if autoimmune hepatitis is suspected; treatment with immunosuppressant drugs may be necessary. Concomitant use of hepatotoxic drugs, including non-prescription drugs, dietary supplements, or herbal products may increase the risk for liver injury.

Eczema, immune-mediated reactions, psoriasis

Daclizumab increases the risk of immune-mediated reactions, including autoimmune disorders such as autoimmune hepatitis. The Zinbryta formulation of daclizumab is contraindicated for use in patients with a history of autoimmune hepatitis or other autoimmune disease involving the liver. Single organ and systemic multi-organ inflammatory reactions have been observed, some requiring systemic treatment with corticosteroids. The most common immune-mediated disorders associated with daclizumab are lymphadenopathy such as lymphadenitis and skin reactions such as rashes and dermatitis. Serious events such as infectious complications following these reactions have been reported. Use caution in patients with a history of skin conditions, including eczema or psoriasis, as daclizumab may worsen these conditions. Treatment of skin reactions has required topical or systemic steroids or immunosuppressant drugs. If a patient develops an inflammatory rash, it is recommended that a dermatologist evaluate the patient before the next dose of daclizumab; discontinuation may be necessary. Benign salivary neoplasm, skin reactions, thrombocytopenia, and interstitial lung changes have been observed with lymphadenopathy. The majority of lymphadenopathy cases resolved with or without continued treatment with daclizumab. If a lymph node biopsy is considered, full diagnostic evaluation should be conducted by a specialist. Immune-mediated colitis and autoimmune hemolytic anemia have also been reported. Consider discontinuing daclizumab and referring patients who develop symptoms of colitis or hemolytic anemia to a specialist. For any suspect immune-related disorder, provide clinically appropriate evaluation to confirm etiology and if necessary refer the patient to an appropriate specialist for treatment.

Common Brand Names

ZINBRYTA

Dea Class

Rx

Description

Immunosuppressant; chimeric monoclonal antibody (IgG1)
Previously approved for relapsing forms of muiltiple sclerosis
Withdrawn form the worldwide market due to safety concerns, including brain inflammation, hepatotoxicity, and other immune-mediated disorders

Dosage And Indications
For the treatment of relapsing forms of multiple sclerosis. Subcutaneous dosage Adults

NOTE: This drug is discontinued in the U.S. Zinbryta was withdrawn from the worldwide market in March 2018 due to safety concerns. The labeled dosage was: 150 mg injected subcutaneously once monthly. If a dose is missed, inject it as soon as possible. If a dose is more than 2 weeks late, skip the missed dose and administer the next dose on schedule. In the U.S., use in multiple sclerosis patients was previously limited to patients who did not respond to prior therapies because of safety concerns associated with use. Daclizumab was reserved for patients who had an inadequate response to 2 or more drugs indicated for multiple sclerosis treatment due to a risk of hepatic injury and immune mediated disorders.

Dosing Considerations
Hepatic Impairment

Daclizumab (Zinbryta) is contraindicated in pre-existing hepatic disease or hepatic impairment including ALT or AST at least 2 times the ULN.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

Azathioprine: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression.
Baricitinib: (Major) Do not use baricitinib in combination with potent immunosuppressants such as daclizumab. A risk of added immunosuppression exists when baricitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose baricitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Basiliximab: (Minor) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents.
Carboplatin: (Minor) Concurrent use of carboplatin with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Chlorambucil: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
Cyclosporine: (Minor) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression.
Daunorubicin: (Minor) Concurrent use of daunorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Doxorubicin: (Major) Concurrent use of doxorubicin with other agents which cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like daclizumab. Although documentation is lacking, use of echinacea during therapy with immunosuppressants is not recommended by some resources.
Infliximab: (Moderate) Many serious infections during infliximab therapy have occurred in patients receiving concurrent immunosuppressives that, in addition to their underlying Crohn's disease or rheumatoid arthritis, predisposes patients to infections.
Live Vaccines: (Severe) Do not administer live vaccines to daclizumab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving daclizumab. At least 2 weeks before initiation of daclizumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Daclizumab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Melphalan: (Minor) Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. The bone marrow depressant effects of melphalan can be potentiated by concurrent or sequential administration of other bone marrow depressants and immunosuppressives.
Mycophenolate: (Minor) Because mycophenolate mofetil is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. Of note, tacrolimus is a potent inhibitor of UDP-glucuronosyl transferase (UDPGT). As mycophenolic acid is metabolized by UDPGT, increased concentrations of mycophenolic acid would be anticipated (see Mechanism of Action).
Natalizumab: (Major) Natalizumab should not be used in combination with daclizumab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab. No formal studies have studied the combination of daclizumab and natalizumab.
Ocrelizumab: (Major) Avoid use of these drugs together. Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis. Concomitant use of ocrelizumab with any of these therapies may increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as daclizumab. The elimination half-life of daclizumab is approximately 20 days.
Sirolimus: (Moderate) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. In a randomized trial of daclizumab for the prevention of allograft rejection in cardiac transplant patients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving daclizumab compared to those receiving placebo (7% vs. 5%, respectively, at 6 months; 10% vs. 6%, respectively, at 12 months). Some, but not all of the increased mortality appeared to be related to a higher incidence of severe infections. Concomitant use of antilymphocyte antibody therapy may also be a factor in some of the fatal infections. In renal allograft recipients treated with daclizumab and mycophenolate mofetil, no pharmacokinetic interaction between daclizumab and mycophenolic acid (the active metabolite of mycophenolate mofetil) was observed. Very limited experience exists with the use of daclizumab concomitantly with antithymocyte globulin, antilymphocyte globulin, muromonab-CD3, or tacrolimus.
Tacrolimus: (Minor) Because daclizumab is an immunosuppressant, additive effects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies including lymphoma and leukemia, myelodysplastic syndromes, and lymphoproliferative disorders. The risk is related to the intensity and duration of immunosuppression rather than the specific agents. In a randomized trial of daclizumab for the prevention of allograft rejection in cardiac transplant patients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving daclizumab compared to those receiving placebo (7% vs. 5%, respectively, at 6 months; 10% vs. 6%, respectively, at 12 months). Some, but not all of the increased mortality appeared to be related to a higher incidence of severe infections. Concomitant use of antilymphocyte antibody therapy may also be a factor in some of the fatal infections. In renal allograft recipients treated with daclizumab and mycophenolate mofetil, no pharmacokinetic interaction between daclizumab and mycophenolic acid (the active metabolite of mycophenolate mofetil) was observed. Very limited experience exists with the use of daclizumab concomitantly with antithymocyte globulin, antilymphocyte globulin, muromonab-CD3, or tacrolimus.
Temozolomide: (Minor) Concurrent use of temozolomide with other agents that cause bone marrow or immune suppression such as other antineoplastic agents or immunosuppressives may result in additive effects.
Tocilizumab: (Major) Avoid using tocilizumab with biological immunosuppressive agents because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological DMARDs such as daclizumab has not been studied. Daclizumab is a biologic monoclonal antibody binds specifically to the alpha subunit of the human high-affinity interleukin (IL)-2 receptor, producing immunosuppression.
Tofacitinib: (Major) Do not use tofacitinib in combination with potent immunosuppressants such as daclizumab. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Upadacitinib: (Major) Do not use upadacitinib in combination with potent immunosuppressants such as daclizumab. A risk of added immunosuppression exists when upadacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose upadacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.

How Supplied

ZINBRYTA Subcutaneous Inj Sol: 1mL, 150mg

Maximum Dosage
Adults

1 mg/kg/dose IV for kidney transplant rejection prophylaxis; 150 mg/month subcutaneously for multiple sclerosis.

Geriatric

1 mg/kg/dose IV for kidney transplant rejection prophylaxis; 150 mg/month subcutaneously for multiple sclerosis.

Adolescents

1 mg/kg/dose IV for kidney transplant rejection prophylaxis. Safety and efficacy of subcutaneous use not established.

Children

1 mg/kg/dose IV for kidney transplant rejection prophylaxis. Safety and efficacy of subcutaneous use not established.

Infants

>= 11 months: 1 mg/kg/dose IV for kidney transplant rejection prophylaxis. Safety and efficacy of subcutaneous use not established.
< 11 months: Safety and efficacy have not been established.

Mechanism Of Action

Daclizumab binds to the alpha-subunit of the interleukin (IL)-2 receptor (IL-2Ra) and inhibits the binding of IL-2 to IL-2Ra. By inhibiting the binding of IL-2 to this receptor, T-cell activation is blocked. The IL-2Ra is only expressed on the surface of activated T-cells and is important in the clonal expansion of activated T-cells. Activation of lymphocytes is a critical pathway in the cellular immune response involved in allograft rejection. The effect of daclizumab differs from that of cyclosporine in that cyclosporine inhibits interleukin-2 release while daclizumab acts as an IL-2 receptor antagonist. Daclizumab does not appear to significantly change circulating lymphocyte numbers or cell phenotypes. While in the systemic circulation, daclizumab impairs the normal 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 daclizumab is cleared is unknown.

Pharmacokinetics

Daclizumab is administered intravenously or subcutaneously. The volume of distribution of daclizumab is relatively small, with a Vd of roughly 2.5 L in the central compartment and 3.4 L in the peripheral compartment. Systemic clearance of daclizumab is low and influenced to a small degree by body weight, which supports dosing on a mg/kg basis. The elimination half-life of daclizumab is roughly 20 days (range: 11 to 38 days), which is similar to the terminal elimination half-life for human IgG (18 to 23 days). Daclizumab clearance in patients who developed neutralizing antibodies was 19% higher.

Intravenous Route

In clinical trials using daclizumab 1 mg/kg IV every 14 days for 5 doses, peak serum concentrations were 21 mcg/mL after the first dose and 32 mcg/mL after the fifth dose. The mean trough serum concentration before the fifth dose was 7.6 mcg/mL. In vitro and in vivo data suggest that a serum daclizumab concentration of 5 mcg/mL to 10 mcg/mL is needed to saturate the Tac subunit of the IL-2 receptor and block the response of activated T-cells. The usual dosage regimen of daclizumab (i.e., 1 mg/kg every other week for 5 weeks) maintains sufficient serum concentrations to provide immunosuppressive activity for at least the first four months (120 days) post-transplant. The duration of clinically-significant IL-2 receptor blockade, however, is not known.

Subcutaneous Route

Following a single subcutaneous injection of daclizumab, maximum concentrations occurred at 5 to 7 days. The mean maximum concentration (Cmax) was 30 mcg/mL, the mean minimum concentration was (Cmin) 15 mcg/mL, and the AUC over the dosing interval was approximately 640 mcg/days/mL. The absolute bioavailability of a 150 mg dose is approximately 90%. Serum concentrations reached steady state by the fourth dose with monthly dosing.

Pregnancy And Lactation
Pregnancy

There are no adequate data on the developmental risk associated with daclizumab use in pregnancy. The IL-2 receptor may play an important role in the development of the immune system, and IgG molecules are known to cross the placental barrier. Administration of daclizumab subcutaneously to monkeys during organogenesis resulted in embryofetal death and reduced fetal growth at maternal exposures more than 30 times that expected clinically.

There is no information regarding the presence of daclizumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for daclizumab and any potential adverse effects on the breast-fed child from daclizumab or the underlying maternal condition.