Dosing and uses of Zinbryta (daclizumab)
Adult dosage forms and strengths
solution for injection
- 150mg/mL in a single-dose prefilled syringe
Multiple Sclerosis
Indicated for adults with relapsing forms of multiple sclerosis (MS)
150 mg SC once monthly (see Administration)
Dosage modifications
Preexisting hepatic impairment including ALT/AST ≥2 x ULN: Contraindicated
Elevated liver enzymes during treatment
- Lab values
- ALT/AST >5 x ULN, OR
- Total bilirubin >2 x ULN, OR
- ALT/AST ≥3 but <5 x ULN and total bilirubin &1.5 bu <2 x ULN
Recommendations
- Interrupt daclizumab therapy and investigate for other etiologies of abnormal lab value(s)
- If no other etiologies identified, then discontinue daclizumab
- If other etiologies are identified, reassess overall risk-benefit profile of daclizumab and consider whether to resume drug when both AST or ALT are <2 x ULN and total bilirubin is ≤ULN
- In clinical trials, permanent discontinuation of therapy was required if the patient had liver test abnormalities resulting in suspension of study treatment for at least 8 consecutive weeks
Dosing Considerations
Because of its safety profile (ie, risk of hepatic injury and immune-mediated disorders), daclizumab is generally reserved for patients who have inadequate response to ≥2 other drugs for Ms
Assessment prior to initiating
- Hepatic assessment
- Evaluate serum transaminases (ALT, AST) and total bilirubin levels
- Initiation is contraindicated with preexisting hepatic disease or hepatic impairment including ALT or AST ≥2 x ULN (see Contraindications)
- Assess for tuberculosis (TB) and other infections
- Evaluate patients at high risk for TB prior to initiating treatment
- For patients testing positive for TB, treat TB by standard medical practice prior to therapy with daclizumab
- Avoid initiating in patients with TB or other severe active infection (see Cautions)
- Prior to initiation, screen patients for Hepatitis B and C (contraindicated with preexisting hepatic disease)
- Vaccinations
- Vaccination with live vaccines is not recommended during treatment and up to 4 months after discontinuation of treatment
- Consider any necessary immunization with live vaccines prior to treatment
Laboratory testing and monitoring
- Test transaminase levels and total bilirubin monthly and assess before the next dose of daclizumab; follow transaminase levels and total bilirubin monthly for 6 months after the last dose
Pediatric dosage forms and strengths
<17 years: Safety and efficacy not established
Not recommended in pediatric patients due to the risks of hepatic injury and immune-mediated disorders
Zinbryta (daclizumab) adverse (side) effects
>10%
Immune-mediated disorders (28-32%)
Nasopharyngitis (25%)
Skin reactions (19%)
Upper respiratory tract infection (9-17%)
Rash (9-11%)
1-10%
Influenza (9%)
Oropharyngeal pain (8%)
Bronchitis (7%)
Depression (7%)
Pharyngitis (6%)
Increased ALT or AST >5 x ULN (4-6%)
Eczema (5%)
Lymphadenopathy (5%)
Rhinitis (4%) Tonsillitis (4%)
Anemia (3%)
Pyrexia (3%)
Dermatitis (3%)
Acne (3%)
Seizures (1%)
<1%
Serious drug-related hepatic injury (0.7%)
Autoimmune hepatitis (0.3%)
Warnings
Black box warnings
Hepatic injury
- Can cause severe liver injury including life-threatening events, liver failure, and autoimmune hepatitis
- In clinical trials, 1 patient died due to autoimmune hepatitis
- Liver injury, including autoimmune hepatitis, can occur at any time during treatment, with cases reported up to 4 months after the last dose
- Contraindicated with preexisting hepatic disease or hepatic impairment
- Before initiating, obtain serum transaminases (ALT and AST) and bilirubin levels
- Test transaminase levels and total bilirubin monthly and assess before the next dose of daclizumab; follow transaminase levels and total bilirubin monthly for 6 months after the last dose
- In case of elevation in transaminases or total bilirubin, treatment interruption or discontinuation may be required
Other immune-mediated disorders
- In addition to autoimmune hepatitis, immune-mediated disorders (eg, skin reactions, lymphadenopathy, noninfectious colitis) can occur
- Overall, serious immune-mediated conditions were observed in 5% of treated patients
- If a serious immune-mediated disorder develops, consider stopping daclizumab and refer the patient to a specialist to ensure comprehensive diagnostic evaluation and appropriate treatment
Treating autoimmune hepatitis or other immune-mediated disorders
- Some patients required systemic corticosteroids or other immunosuppressant treatment for autoimmune hepatitis or other immune-mediated disorders and continued this treatment after the last dose of daclizumab
Restricted access program
- Because of the risks of hepatic injury, including autoimmune hepatitis, and other immune-mediated disorders, daclizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZINBRYTA REMS Program
Contraindications
Preexisting hepatic disease or hepatic impairment, including ALT or AST at least 2 x ULN; daclizumab exacerbate existing liver dysfunction (see Black box warnings)
History of autoimmune hepatitis or other autoimmune condition involving the liver (see Black box warnings)
History of hypersensitivity; use may result in anaphylaxis or life-threatening multiorgan hypersensitivity
Cautions
Can cause life-threatening severe liver injury, including liver failure and autoimmune hepatitis (see Black box warnings, Contraindications, and Dosage modifications)
Immune-mediated disorders reported, including autoimmune hepatitis, skin reactions, lymphadenopathy, and noninfectious colitis (see Black box warnings, Contraindications)
Available only through a restricted access program (see Black box warnings)
Can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time during treatment; discontinue and do not restart if anaphylaxis or other allergic reactions occur (see Contraindications)
Increased risk for infection; avoid initiating in patients with severe active infection until infection is fully controlled; assess for preexisting infections (eg, TB, hepatitis B or C) before initiating
Depression-related events occurred more frequently in patients receiving daclizumab compared with control or placebo in clinical trials; caution in patients with history of depression and/or suicidal ideation; consider discontinuing is severe depression occurs
Drug interaction overview
- Caution should be used if hepatotoxic drugs are coadministered, including nonprescription products
- Avoid use of herbal products or dietary supplements that can cause hepatotoxicity
- Vaccination with live vaccines is not recommended during treatment and up to 4 months after discontinuation
Pregnancy
Pregnancy
There are no adequate data on the developmental risk associated with use of daclizumab in pregnant women
Administration of the drug to monkeys during gestation resulted in embryofetal death and reduced fetal growth at maternal exposures >30 times that expected clinically
Lactation
Unknown if distributed in human breast milk
Daclizumab was excreted in the milk of daclizumab-treated monkeys
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Zinbryta (daclizumab)
Mechanism of action
Humanized monoclonal antibody that binds to the high-affinity interleukin-2 (IL-2) receptor subunit (CD25); these subunits are expressed at high levels on T-cells that become abnormally activated in multiple sclerosis
Absorption
Peak plasma time: 5-7 days
Peak plasma concentration (steady-state): 15 mcg/mL
AUC (steady-state): 640 mcg·days/mL
Steady-state reached by fourth dose
Distribution
Vd (steady-state): 6.34 L
Metabolism
Because it is a protein, daclizumab is expected to undergo catabolism to peptides and amino acids in the same manner as endogenous IgG proteins without renal elimination
Elimination
Half-life: 21 days
Clearance: 0.212 L/day; 19% higher with neutralizing antibodies
Administration
SC Preparation
Train patients in the proper technique for self-administering SC injections using the prefilled syringe
30 minutes prior to injection, remove daclizumab from the refrigerator to allow the drug to warm to room temperature
Do not use external heat sources such as hot water to warm the prefilled syringe
Do not place daclizumab back into the refrigerator after allowing it to warm to room temperature
Parenteral drug products should be inspected visually for particulate matter and discoloration
Solution should appear as colorless to slightly yellow and clear to slightly opalescent
Do not use if solution is cloudy or there are visible particles
SC Administration
For subcutaneous (SC) use only
Sites for injection include the thigh, abdomen, and back of the upper arm
Use each prefilled syringe 1 time and then place in a sharps disposal container for disposal according to community guidelines
Missed dose
- Instruct patients to inject a missed dose as soon as possible but no more than 2 weeks late
- After 2 weeks, skip the missed dose and take the next dose on schedule
- Administer only 1 dose at a time; do not double the dose
Storage
Refrigerate between 2-8°C (36-46°F) in the original carton to protect from light
Do not freeze; discard if frozen
Do not expose to temperatures >30°C (86°F)
If refrigeration is unavailable, may store protected from light up to 30°C (86°F) for a period up to 30 days
Do not place drug back into the refrigerator after allowing it to warm to room temperature
Discard after 30 days without refrigeration
