Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: BIOGEN IDEC Limited, Innovation House, 70 Norden Road, Maidenhead, Berkshire, SL6 4AY, United Kingdom
Zinbryta is contraindicated in patients with a history of severe hypersensitivity (e.g. anaphylaxis or anaphylactoid reactions) to all forms of daclizumab or to any of the excipients in Zinbryta (see section 6.1).
Pre-existing hepatic disease or hepatic impairment (see section 4.4).
Due to the risk of hepatic injury, the use of Zinbryta is restricted (see section 4.1). Serious hepatic injury including elevations of serum transaminases and fatal cases of autoimmune hepatitis and fulminant liver failure have occurred in patients treated with Zinbryta (see section 4.8). Cases occurred early after treatment initiation, in patients having received repeated treatment courses and several months after discontinuation.
Prior to treatment initiation with Zinbryta, serum transaminases (ALT and AST) and total bilirubin levels should be obtained, and patients should be screened for Hepatitis B (HBV) and C (HCV). Treatment initiation is not recommended in patients with ALT or AST ≥2 times the upper limit of normal (ULN) and is contraindicated in patients with pre-existing hepatic impairment (see section 4.3). For patients who test positive for HBV or HCV infection, consultation with a physician with expertise in the treatment of HBV or HCV is recommended. Treatment initiation is not recommended in patients with history of concurrent autoimmune conditions other than multiple sclerosis.
Patient serum transaminase and total bilirubin levels should be monitored at least monthly and as close as possible before each administration, and more frequently as clinically indicated during treatment and up to 6 months after the last dose of Zinbryta. Treatment discontinuation is recommended in patients who reach ALT or AST >3 times the ULN regardless of bilirubin levels.
Patients should be informed about the risk of hepatic injury, the need for periodic monitoring and warned about signs or symptoms suggestive of hepatic dysfunction. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction (e.g. unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), it is recommended to promptly measure serum transaminases, discontinue treatment with Zinbryta, as appropriate, and promptly refer the patient to a hepatologist.
Treatment discontinuation should be considered if an adequate response has not been achieved or the patient fails to follow the requirement for scheduled liver test monitoring.
Caution should be exercised when administering medicinal products of known hepatotoxic potential, including non-prescription products and herbal supplements, concomitantly with Zinbryta (see section 4.5).
Refer to section below, ‘Educational Guidance’, for details of the Hepatic Risk Management Guide for Physicians and Patient Card that are recommended for use with this medicine.
All physicians who intend to prescribe Zinbryta must ensure they are familiar with the Hepatic Risk Management Guide for Physicians for this medicinal product.
The physician should discuss the risk of hepatic injury with patients and provide them with a Patient Card.
The Card informs patients of the risk of serious hepatic injury, and its possible symptoms, so that they are aware of situations in which they should contact a healthcare professional in a timely manner. In addition, the Card explains the need for monitoring of liver function and educates the patient on the importance of adherence to their monthly blood tests.
Skin reactions, some serious (e.g. exfoliative rash or dermatitis, toxic skin eruption), have been reported with Zinbryta. Skin reactions generally resolved with standard care, including treatment with topical or systemic steroids. If a patient develops a diffuse or highly inflammatory rash, referral to a dermatologist and discontinuation of Zinbryta may be required (see section 4.8).
Zinbryta should be administered with caution to patients with previous or current depressive disorders. Patients treated with Zinbryta should be advised to report any symptoms of new or worsening depression, and/or suicidal ideation immediately to the prescribing physician. If a patient develops severe depression, and/or suicidal ideation, discontinuation of Zinbryta should be considered (see section 4.8).
Infections, some serious (e.g. pneumonia and bronchitis), have been reported with Zinbryta. If serious infection develops, it could be necessary to withhold treatment with Zinbryta until the infection resolves.
Tuberculosis infections have been reported in patients treated with Zinbryta. In patients who have had tuberculosis or who live in endemic areas of the disease, screening for active tuberculosis should be performed before starting treatment, and patients should be monitored during treatment.
In patients with severe active infection, a delay in initiation of Zinbryta therapy should be considered (see section 4.8).
Zinbryta has not been studied in patients with immunodeficiency syndromes.
Autoimmune haemolytic anaemia has been reported in patients treated with Zinbryta which resolved with standard treatment and discontinuation of Zinbryta. If a patient develops signs or symptoms of autoimmune haemolytic anaemia (e.g. pallor, fatigue, dark urine, jaundice, shortness of breath), consider referring to a specialist and discontinuing Zinbryta (see section 4.8).
Colitis has been reported with Zinbryta. The colitis improved with discontinuation of Zinbryta and standard treatment. Referring patients who develop symptoms of colitis (e.g. abdominal pain, fever, prolonged diarrhoea) to a specialist is advisable (see section 4.8).
When observed during Zinbryta clinical studies, lymphopenia was mostly mild to moderate (≥500/mm³). Sustained severe lymphopenia (<500/mm³), was not observed in clinical studies with Zinbryta. However, as a precaution, monitoring of complete blood count is recommended every 3 months.
The risk of Progressive Multifocal Leukoencephalopathy (PML) associated to the treatment with Zinbryta has not been established.
This medicinal product contains 0.14 mmol sodium per dose. It is essentially ‘sodium-free’ and can be used by patients on a sodium-restricted diet.
Zinbryta is not expected to undergo metabolism by hepatic enzymes or renal elimination. There is limited data on concomitant use of Zinbryta with MS symptomatic therapies.
Cases of hepatic injury have occurred in patients taking Zinbryta with other hepatotoxic drugs, although the role of these medicinal products is uncertain. Caution is recommended when administering medicinal products of known hepatotoxic potential including non-prescription products and herbal supplements concomitantly with Zinbryta (see section 4.4).
The safety of immunisation with live viral vaccines during treatment with Zinbryta has not been studied. Vaccination with live vaccines is not advised during treatment and up to 4 months after discontinuation.
In a clinical study, patients (n=90) on long-term treatment with Zinbryta mounted appropriate immune responses to an inactivated trivalent seasonal influenza vaccine. The magnitude of the immune response to the seasonal influenza vaccine, and proportion of patients with seroconversion and seroprotection were consistent with those observed in healthy volunteer populations. Patients on Zinbryta may receive non-live vaccines.
There are limited data from the use of Zinbryta in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reprotoxicity (see section 5.3). Zinbryta should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Available toxicology data in lactating cynomolgus monkeys have shown excretion of daclizumab beta in milk (for details see section 5.3). It is not known whether Zinbryta is secreted in human milk. Although human IgG is secreted into human milk, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. A risk to newborns/infants cannot be excluded.
If a woman wishes to breast-feed during treatment with Zinbryta, the benefit of breast-feeding to the child and of therapy to the woman should be considered.
No impact on male or female fertility as assessed by fertility indices was detected in animal studies (see section 5.3). There are no data on the effects of Zinbryta on human fertility.
Zinbryta has no or negligible influence on the ability to drive and use machines.
In the placebo-controlled study (the SELECT study), 417 patients received Zinbryta (150 mg, n=208; 300 mg, n=209; every 4 weeks) for up to 1 year. In the active-controlled study (the DECIDE study), 919 patients received Zinbryta (150 mg, every 4 weeks) and 922 patients received interferon beta-1a intramuscular, (30 microgram weekly) for a minimum of 2 years and up to 3 years.
The most commonly reported adverse reactions leading to discontinuation in patients treated with Zinbryta were hepatic reactions, including elevations of serum transaminases (5%), and cutaneous reactions (4%) (see section 4.4).
The most common adverse reactions reported for Zinbryta were rash, increased alanine aminotransferase (ALT), depression, nasopharyngitis, upper respiratory tract infection, influenza, oropharyngeal pain, and lymphadenopathy.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Order Class by frequency and incidence. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The incidence of the adverse reactions is expressed according to the following categories: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10, 000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Table 1. Adverse reactions reported for Zinbryta 150mg:
Very Common: Upper respiratory tract infection†, Nasopharyngitis†
Common: Pneumonia, Respiratory tract infection, Bronchitis, Viral infection, Influenza†, Laryngitis, Tonsillitis†, Pharyngitis, Folliculitis, Rhinitis*
Common: Lymphadenopathy†, Lymphadenitis, Anaemia*
Uncommon: Autoimmune haemolytic anaemia
Uncommon: Sarcoidosis
Common: Depression*
Common: Oropharyngeal pain†
Common: Diarrhoea, Colitis
Common: Dermatitis, Dermatitis allergic, Eczema†, Psoriasis, Seborrhoeic dermatitis†, Skin exfoliation, Rash*†, Rash maculopapular, Acne†, Erythema, Pruritus, Dry skin
Uncommon: Exfoliative rash, Toxic skin eruption, Eczema nummular
Common: Pyrexia*
Very common: Transaminases increased
Uncommon: Autoimmune hepatitis
Not known: Fulminant hepatitis
Very common: Liver function test abnormal
Common: Lymphocyte count decreased
* Observed with a ≥2% higher incidence than placebo
† Observed with a ≥2% higher incidence than interferon beta-1a (intramuscular)
Serious hepatic injury, including fatal cases of autoimmune hepatitis and fulminant liver failure have occurred in patients treated with Zinbryta. Serious reactions, including autoimmune hepatitis, hepatitis and jaundice, were observed in 1.7% of patients in clinical trials.
In clinical studies, serum transaminase elevations occurred at any time during treatment and up to 6 months after the last dose of Zinbryta. Most patients had mild elevations that were below or up to 3 x ULN and resolved spontaneously. In clinical trials, an increased incidence of elevations of ALT or AST was reported more frequently in Zinbryta-treated patients compared to placebo or interferon beta-1a (intramuscular). The incidence of discontinuation due to medicine related hepatic disorders was 5% in Zinbryta-treated patients and 4% in interferon beta-1a (intramuscular).
Table 2. Cumulative incidences of peak ALT or AST increase (based on laboratory data) observed in clinical trials:
| Daclizumab 150 mg (N=1943) | Interferon beta-1a (N=922) | Placebo (N=204) | |
|---|---|---|---|
| Total exposure (subject-years) | 7011 | 1884 | 210 |
| ≥3 x ULN | 13.6% | 8.5% | 3.4% |
| >5 x ULN | 9.0% | 3.4% | 0.5% |
| >10 x ULN | 4.3% | 1.3% | 0.0% |
| >20 x ULN | 1.4% | 0.4% | 0.0% |
| AST ή ALT ≥3 x ULN AND total bilirubin ≥ x 2 ULN | 0.77% | 0.1% | 0.5% |
In clinical studies Zinbryta increased the incidence of skin reactions [18% vs 13% (placebo); 37% vs 19% (interferon beta-1a (intramuscular))] and serious skin reactions [<1% vs 0% (placebo); 2% vs <1% (interferon beta-1a (intramuscular))] compared to placebo and interferon beta-1a (intramuscular).
The most common skin reactions were rash, dermatitis, and eczema. The majority of patients had skin reactions that were mild or moderate in severity. Discontinuation due to skin reactions was 4% in Zinbryta-treated patients.
In clinical studies, Zinbryta increased the incidence of depression [5% vs 1% (placebo); 8% vs 6% (interferon beta-1a (intramuscular))]; the incidence of serious reactions of depression was <1% with Zinbryta.
In clinical studies, Zinbryta increased the incidence of infections [50% vs 44% (placebo) and 65% vs 57% (interferon beta-1a (intramuscular))] and serious infections [3% vs 0% (placebo); 4% vs 2% (interferon beta-1a (intramuscular))] compared to placebo and interferon beta-1a (intramuscular). The most common types of infections were upper respiratory tract infections and viral infections. The median duration was similar between the treatment groups. The rate of infections and serious infections did not increase over time. The majority of patients with infections continued on treatment with Zinbryta. Discontinuation of Zinbryta due to infections was <1%.
Autoimmune haemolytic anaemia was reported in <1% of patients treated with Zinbryta in clinical studies.
An increased incidence of serious colitis (<1%) was reported in patients treated with Zinbryta in clinical studies.
In clinical studies, Zinbryta increased the incidence of lymphadenopathy, with onset occurring throughout the treatment period. Discontinuation due to lymphadenopathy was <1% in Zinbryta-treated patients. The majority of patients with lymphadenopathy continued on treatment with Zinbryta, and the majority of cases resolved within 3 months.
In the DECIDE study (see section 5.1), patients were tested for anti-drug (daclizumab beta) antibodies at week 4 and approximately every 3 months thereafter. Treatment-emergent anti-drug antibodies and neutralising antibodies were observed in 19% (175/913) and 8% (71/913) of study patients, respectively. The majority of the treatment-emergent anti-drug antibodies responses were transient (12% [110/913]) and the remaining minority (7% [65/913]) were persistent. Among the evaluable patients, the majority of treatment-emergent neutralising antibody responses were transient (6% [56 of 913]) and 2% of patients (15 of 913) had persistent responses. Treatment-emergent anti-drug antibodies and neutralising antibodies responses predominantly occurred during the first year of treatment and their frequency declined with continued Zinbryta treatment.
In patients with neutralising antibodies, daclizumab beta clearance was increased on average by 19% (see section 5.2). There was no apparent correlation of anti-drug antibodies or neutralising antibodies development to clinical response, adverse reactions, or pharmacodynamic profile of daclizumab beta.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product should not be mixed with other products.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
