Side Effects of Zinbryta (daclizumab)

Zinbryta (daclizumab) is an interleukin-2 receptor blocking antibody used to treat multiple sclerosis (MS). Its mechanism of action is not completely understood. 

Available data suggest that it may work by modifying immune processes that may be responsible for causing MS by interfering with the activation of lymphocytes (a type of white blood cell) that cause inflammation and destruction of nerves in patients with MS. 

Zinbryta does not cure MS. It decreases the number of MS flares and lesions. It is reserved for patients who have had an inadequate response to two or more MS drugs because of its safety profile.

Common side effects of Zinbryta include

• cold symptoms,
• upper respiratory tract infection,
• rash,
• flu,
• dermatitis,
• throat pain,
• bronchitis,
• eczema,
• depression,
• sore throat,
• increased alanine aminotransferase (alt),
• tonsillitis,
• acne,
• anemia, and
• fever.

Serious side effects of Zinbryta include

• liver damage,
• immune-mediated disorders (for example, skin reactions, colitis),
• serious allergic reactions (anaphylaxis, angioedema),
• severe infections,
• depression,
• suicidal thoughts,
• suicide,
• decreased numbers of white blood cells,
• severe skin reactions, and
• non-infectious colitis.

Drug interactions of Zinbryta include prescription drugs, non-prescription drugs, herbal products, or dietary supplements that affect the liver because it may increase the risk of liver damage. Such combinations should be avoided when possible or used cautiously. 

Zinbryta has not been adequately evaluated in pregnant women. There is no information about the secretion of Zinbryta in breast milk. Consult your doctor before breastfeeding.

Common side effects include:

• Cold symptoms
• Upper respiratory tract infection
• Rash
• Flu
• Dermatitis
• Throat pain
• Bronchitis
• Eczema
• Depression
• Sore throat
• Increased alanine aminotransferase (ALT)

Other side effects include:

• Tonsillitis
• Acne
• Anemia
• Fever

Other less common side effects include:

• Increased levels of liver enzymes
• Diarrhea
• Dry skin
• Skin redness (erythema)
• Folliculitis
• Psoriasis
• Skin exfoliation
• Toxic skin eruption
• Viral infection

Possible serious side effects include:

• Liver damage
• Immune mediated disorders (for example, skin reactions, colitis)
• Serious allergic reactions (anaphylaxis, angioedema)
• Severe infections
• Depression
• Suicidal thoughts, Suicide
• Decreased numbers of white blood cells
• Severe skin reactions
• Non-infectious colitis

The following serious adverse reactions are described elsewhere in labeling:

• Hepatic Injury
• Immune-Mediated Disorders
• Acute Hypersensitivity
• Infections
• Depression and Suicide

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Zinbryta cannot be directly compared with rates in clinical trials of other drugs and may not reflect the rates observed in practice.
• In all controlled and uncontrolled trials performed in patients with relapsing multiple sclerosis, 2236 patients received Zinbryta for a total of 5214 person-years.
• Of these patients, 1576 received Zinbryta for at least 1 year, 1259 for at least 2 years, and 888 for at least 3 years.
• In the controlled studies, approximately 67% were female, 92% were Caucasian, and the mean age was 36 years at study entry.
• In the active-controlled study (Study 1), 919 patients received Zinbryta (150 mg SQ, every 4 weeks) and 922 patients received AVONEX (interferon beta-1a 30 mcg IM, weekly) for a minimum of 2 years and up to 3 years, with 1952 person-years of exposure to Zinbryta; the median length of treatment was approximately 27 months. The adverse reactions from Study 1 are presented in Table 2.
• In the placebo-controlled study (Study 2), 417 patients received Zinbryta with 423 person-years of exposure, of which 208 received 150 mg, and 204 received placebo every 4 weeks for up to 1 year; the median length of treatment was approximately 11 months. The adverse reactions from Study 2 are presented in Table 3.
• The most common adverse reactions (incidence at least 5% and at least 2% higher incidence than comparator) that occurred in Zinbryta-treated patients were
  • nasopharyngitis,
  • upper respiratory tract infection,
  • rash,
  • influenza,
  • dermatitis,
  • oropharyngeal pain,
  • bronchitis,
  • eczema, and
  • lymphadenopathy compared with AVONEX; and
  • upper respiratory tract infection,
  • depression,
  • rash,
  • pharyngitis, and
  • increased alanine aminotransferase (ALT) compared with placebo.
• The most common adverse reactions leading to discontinuation in up to 5% of patients treated with Zinbryta were hepatic events including elevations of serum transaminases and cutaneous events.
• Patients were excluded from the clinical studies for abnormal laboratory values including hemoglobin, complete blood count with differential, serum transaminases, or serum creatinine.
• Patients were excluded if they had a history of seizure disorder or of having a seizure within 6 months of beginning the study, or suicidal ideation or severe depression within 3 months of beginning the study.
• During Study 1, concomitant use of Zinbryta with the hepatotoxic drugs valproic acid, carbamazepine, lamotrigine, phenytoin, isoniazid, and propylthiouracil was not permitted except in patients already receiving the drugs at the time of study entry.
• In clinical studies, serum chemistry was evaluated at baseline and monthly.
• Hematology was evaluated at baseline, monthly for 6 months, and then every 3 months. Thyroid function was measured at baseline and every 6 months.

Table 2: Adverse Reactions in Adults with RMS with an Incidence at Least 2% More for Zinbryta 150 mg SQ Every 4 Weeks than AVONEX 30 mcg IM Once Weekly (Study 1)

Table 3: Adverse Reactions in Adults with RMS with an Incidence at Least 2% More for Zinbryta 150 mg SQ Every 4 Weeks than Placebo (Study 2)

Other clinically relevant adverse reactions observed at <2% difference included

• abnormal liver function test,
• decreased lymphocyte count,
• diarrhea,
• dry skin,
• erythema,
• folliculitis,
•  increased hepatic enzyme,
• laryngitis,
• lymphadenitis,
• pneumonia,
• pruritus,
• psoriasis,
• respiratory tract infection,
• skin exfoliation,
• toxic skin eruption, and
• viral infection.

Seizures

• In Study 1, seizures occurred in 1% of Zinbryta-treated patients, compared with 0.3% of AVONEX-treated patients.
• In Study 2, no seizures occurred in either treatment group.

Immune-Mediated Disorders

• Types of immune-mediated or autoimmune conditions that were observed in 2 or more Zinbryta-treated patients include
  • type I diabetes,
  • celiac disease,
  • autoimmune thyroiditis,
  • immune hemolytic anemia,
  • thrombocytopenia,
  • pancreatitis,
  • glomerulonephritis,
  • sarcoidosis,
  • rheumatoid arthritis,
  • thyroiditis, and
  • sialadenitis.
• The relationship of these events to Zinbryta is unknown.

Breast Cancer

• In controlled studies, 1 Zinbryta-treated woman developed breast cancer compared with none in the AVONEX-treated group.
• Across all controlled and open-label clinical studies, 8 of 1485 (0.5%) Zinbryta-treated women developed breast cancer, and 1 of 751 (0.1%) Zinbryta-treated men developed breast cancer.
• It is unclear whether this represents an incidence increase over background rate.

Immunogenicity

• As with all therapeutic proteins, there is potential for immunogenicity.
• In Study 1, patients were tested for anti-drug (daclizumab) antibodies at Week 4 and approximately every 3 months thereafter.
• Anti-drug antibodies and neutralizing antibodies were observed in 19% (175/913) and 8% (71/913) of patients, respectively.
• Anti-drug antibody responses were transient in 12% (110/913) of patients and persistent in 7% (65/913) of patients.
• Anti-drug and neutralizing antibody responses predominantly occurred during the first year of treatment, and their frequency declined with continued Zinbryta treatment.
• In patients with neutralizing antibodies, daclizumab clearance was increased on average by 19%.
• There was no apparent correlation of anti-drug antibody or neutralizing antibody development to clinical response, adverse reactions, or pharmacodynamic profile of Zinbryta.
• The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including
  • assay methodology,
  • sample handling,
  • timing of sample collection,
  • concomitant medications, and
  • underlying disease.
• For these reasons, comparison of the incidence of antibodies to daclizumab with the incidence of antibodies to other products may be misleading.

Hepatotoxic Drugs

• Caution should be used when using hepatotoxic drugs, including non-prescription products, concomitantly with Zinbryta.
• Carefully consider the need for the use of herbal products or dietary supplements that can cause hepatotoxicity.