OCREVUS (Ocrelizumab) Konzentrat zur Herstellung einer Infusionslösung, 300mg/10ml Zul.-Nr

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1 OCREVUS (Ocrelizumab) Konzentrat zur Herstellung einer Infusionslösung, 300mg/10ml Zul.-Nr Public Risk Management Plan (RMP) Summary, Version 2.0 Document Date: Based on: EU-RMP Vers. 1.4 and Swiss-specific RMP-Addendum Vers. 1.0

2 The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them. The RMP summary of Ocrevus is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation / Information sur le médicament approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Ocrevus in Switzerland is the Arzneimittelinformation/ Information sur le médicament (see approved and authorized by Swissmedic. Roche Pharma (Schweiz) AG is fully responsible for the accuracy and correctness of the content of the published summary RMP of Ocrevus.

3 VI.2.1. Overview of Disease Epidemiology Multiple Sclerosis (MS) is a disease that affects the central nervous sytem which includes the brain, spinal cord, and optic nerves. In Europe, around 1 in 1000 people have MS. There are several forms of MS. Around 85% of patients with MS have repeated episodes (relapses) caused by the body s immune (protective) system attack on certain cells in the brain and spinal cord called axons which then interferes with the way the central nervous system communicates with the body, causing a wide range of symptoms (relapsing forms of MS; RMS). A less common form (around 10%) is characterized by patients with MS that have symptoms which continuously get worse from the start of the disease (primary progressive MS; PPMS). Occasionally relapses can also occur in PPMS. While relapsing-remitting MS (RRMS) occurs twice as likely in women than in men, PPMS is equally likely in men and women. RRMS typically occurs at a younger age than PPMS (30 years of age for RRMS and 40 years of age for PPMS). VI.2.2 Summary of Treatment Benefits In RMS, Ocrevus helps to suppress relapses and the progression of the disease. In two Phase 3 clinical studies in 821 and 835 patients with RRMS and another relapsing form of MS, Ocrevus reduced the number of relapses by about half compared with patients receiving treatment with Rebif (a beta-interferon 1-a medicine used to treat RRMS) over a 2 year period. Ocrevus also significantly delayed (or slowed down) the progression of physical disability caused by MS by 40% compared with patients receiving Rebif. In addition, Ocrevus nearly completely suppressed gadolinium-enhancing and T2 brain lesions on magnetic resonance imaging (diagnostic pictures of the inside of the body, created using magnetic rather than x-ray energy) compared with Rebif. Lesions in the brain are inflamed or damaged areas. They may appear or grow larger without immediate noticeable consequence but they can also be a sign of irreversible damage that may lead to disability progression. Therefore their suppression is important to reduce disability progression. In PPMS, Ocrevus also significantly delayed (or slowed down) the progression of physical disability and reduced deterioration in walking speed compared with patients receiving placebo (an inactive treatment). In a Phase 3 clinical trial in 732 patients with PPMS over 2 years, Ocrevus reduced the risk of progression of disability by about 25% compared with patients who received the placebo. Ocrevus reduced the risk for deterioration in walking speed by 25% compared with placebo. With the magnetic resonance imaging it can be seen that Ocrevus also slowed the rate of overall brain shrinkage which means that the damaged caused by MS to your brain overall is reduced. Ocrevus also reduced the size of brain lesions in the brain compared with placebo. These described benefits of Ocrevus have been seen in patients with early PPMS i.e. patients that, when they started Ocrevus had an age between 18 and 55 years, an EDSS score between 3 and 6.5 and a duration of PPMS from the first

4 symptoms of less than 10 years or less than 15 years depending if the EDSS score was below or at least 5 respectively. VI.2.3 Unknowns Relating to Treatment Benefits The treatment benefit observed in patients who received Ocrevus was similar in all patients regardless of their characteristics. Ocrevus was not studied in patients older than 55 years, patients with moderate and severe abnormal function of kidneys and liver, congestive heart failure, patients of Asian race, or patients with advanced RMS or PPMS.

5 VI.2.4 Summary of Safety Concerns Important Identified Risks Risk What is known Preventability Infusion reactions (infusion related reactions, IRRs) Infections Around one third of patients with MS treated with Ocrevus in clinical studies experienced reactions related to infusion of the drug. These reactions occur mainly during or within 24 hours after the first infusion.their frequency and severity decreases with later infusions. However, patients who did not have an (infusion related reactions (IRR) during the first infusion can still have an IRR at later infusions. Most reactions are mild or moderate, but some severe and lifethreatening reactions have also been reported. Reactions reported to date include itchy skin, rash, hives, redness of the skin, throat irritation or pain, shortness of breath, swelling of the throat, flushing, low blood pressure, fever, feeling tired, headache, feeling dizzy, feeling sick (nausea), and fast heart beat. Ocrevus depletes certain immune cells (B cells, a type of white blood cell which plays a major role in the immune system response) that may help to fight infection. For this reason, patients may get infections more easily with Ocrevus. Patients are checked (by blood test) to determine the status of their immune system before each Ocrevus infusion. These infections are usually mild infections, but serious infections can happen. The following infections have been seen in patients treated with Ocrevus in MS. Very common: may affect more than 1 in 10 people upper respiratory tract infection common cold The risk of infusion reactions can be reduced by administration of prophylactic medication (pretreatment with corticosteroids and antihistamines is mandatory), and the addition of medicines to reduce fever can also be considered before each infusion of Ocrevus. Patients will be closely monitored during the infusion and for at least one hour after the completion of infusion. Infusion may be slowed down or interrupted should severe symptoms occur and appropriate medication given to treat the symptoms. Patients taking medicines for high blood pressure may have to stop taking these medicines for 12 hours before each Ocrevus infusion. Patients who have another disease that suppresses or modulates the immune system may not be able to receive Ocrevus. Ocrevus administration must be delayed in patients with an active infection until the infection is resolved. Patients should tell their doctor or nurse straight away if they have any of these signs of infection during or after Ocrevus treatment: fever and/or chills cough which does not go away herpes (such as cold sore, shingles or genital sores).

6 Risk What is known Preventability flu Hepatitis B: Patients who have had hepatitis B or are carriers of the hepatitis B virus will have a blood test Common: may affect up to 1 in 10 people and will be monitored by a doctor for signs of hepatitis sinus infection B infection. This is because the virus could become active and may result in serious liver problems. bronchitis (bronchial tube inflammation) herpes infection (cold sore or shingles) infection of the stomach and bowel (gastroenteritis) respiratory tract infection viral infections red and inflamed eye (conjunctivitis) skin infection (cellulitis) Uncommon: may affect up to 1 in 100 people genital sores In patients treated with Ocrevus who have had a type of liver disease called hepatitis B or are carriers of the hepatitis B virus, the virus could become active and may result in serious liver problems. This is because medicines similar to Ocrevus can cause the hepatitis B virus to become active again and this has been fatal in some patients.

7 Important Potential Risks Risk Allergic reaction (hypersensitivity reactions) Cancers including breast cancer (malignancies including breast cancer) Vaccinations may not be effective (impaired immunization response) Brain infection - PML What is known (Including reason why it is considered a potential risk) No patients treated with Ocrevus in clinical studies had an allergic reaction to ocrelizumab or any of the other ingredients. However, there is a possibility patients may experience an allergic reaction to ocrelizumab or any of the other ingredients of this medicine. Patients allergic to ocrelizumab or any of the other ingredients of the medicine must not be treated with Ocrevus. Cancers, including breast cancer, have been reported during the clinical programme, more frequently with Ocrevus than with the comparators, however these numbers were similar to the numbers expected in an MS population. Patients should also be advised to follow standard breast cancer screening per local guidelines. Treatment with Ocrevus may be delayed in patients who currently have cancer or who have had cancer in the past. Patients who know they have another disease that suppresses or modulates the immune system may not be able to receive Ocrevus. The action of ocrelizumab on white blood cells may reduce the effect of vaccination. Patients should tell their doctor if they have recently been given, or might be given in the near future, any sort of vaccine. While being treated with Ocrevus, patients should not be given some types of vaccine, called live or live attenuated vaccines (for example BCG for tuberculosis or vaccines against yellow fever). Therefore, patients should be advised to inform health care professionaly who are planning to vaccinate them, that they are being treated with Ocrevus. In addition to not having live or live-attenuated vaccines during your Ocrevus treatment, it is also not known how Ocrevus may affect their response to other types of vaccines. The doctor will check if the patient needs any vaccinations before starting treatment with Ocrevus. Any vaccinations should be given at least 6 weeks before you start treatment with Ocrevus. A very rare and life-threatening brain infection, called Progressive Multifocal Leukoencephalopathy or PML, which can cause symptoms similar to those of MS, has been seen in patients taking other medicines that are similar to Ocrevus. PML has also been associated with some other MS medications. PML: Patients should tell their partner or caretaker about their Ocrevus treatment. They might notice symptoms that the patient does not, such as memory lapses, trouble thinking, difficulty walking, sight loss, changes in the way you talk, which their doctor may need to investigate. Patients and their carers are advised to tell their doctor if they develop any new or unusual neurological symptoms on ocrelizumab treatment. Patients should tell their doctor if they have ever taken, are taking, or are planning to take medicines that suppress or modulate the immune system such as chemotherapy, immuno-suppressants, or other medicines used to treat MS disease. The effect on the immune system of these medicines with Ocrevus could be too strong. The doctor may decide to delay the treatment with Ocrevus or may ask the patient to stop such medicines before

8 starting treatment with Ocrevus. Serious infection due to low immunoglobulin levels Patient who have low levels of immunoglobulins are at a greater risk of experiencing serious infections. Patients with pre-existing low levels of immunoglobulins may not be able to receive Ocrevus. Patients who have another disease that suppreses or modulates the immune system may not be able to receive Ocrevus. Ocrevus administration must be delayed in patients with an active infection until the infection is resolved. Patients should tell their doctor or nurse straight away if they have any of these signs of infection during or after Ocrevus treatment: fever and/or chills cough which does not go away herpes (such as cold sore, shingles or genital sores). Hepatitis B Reactivation Reactivation of hepatitis B refers to the abrupt increase in hepatitis B virus (HBV) replication in a patient with inactive or resolved hepatitis B. Reactivation can occur spontaneously, but more typically is triggered by immunosuppressive therapy of cancer, autoimmune disease, or organ transplantation. Anti-CD20 Ab therapy therefore may trigger HBV reactivation in patients with a history of HBV infection, however, no such reports in MS patients treated with Ocrelizumab/Ocrevus were reported. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has been reported in patients treated with other anti-cd20 antibodies. The majority of patients received RTX in combination with chemotherapy. In general Hepatitis B Reactivation is part of the infection risk which is linked to the mechanism of action of Ocrelizumab/Ocrevus.

9 Missing Information Risk Use in pregnancy and breastfeeding (use in pregnancy and lactation) What is known Ocrevus has not been studied in pregnant or breastfeeding women. Patients must tell their doctor before being given Ocrevus if they are pregnant, think that they might be pregnant or are planning to have a baby. This is because Ocrevus may cross the placenta and affect the baby. Pregnant women should not use Ocrevus unless they have discussed this with their doctor. The doctor will consider the benefit of you taking Ocrevus against the risk to the baby. Women who are able to become pregnant (conceive) must use contraception (adequate forms of birth control): during treatment with Ocrevus and for 12 months after the last infusion of Ocrevus Women should not breastfeed while being treated with Ocrevus. This is because ocrelizumab may pass into breast milk. Use in children (use in paediatric population) Use in patients older than 55 years (including elderly) Ocrevus has not been studied in children and adolescents under 18 years old and should not be used in children and adolescents under 18 years old. Only patients aged between 18 and 55 years at study screening could enrol in MS studies with ocrelizumab.

10 Risk Long-term safety of Ocrevus treatment Safety of Ocrevus together with any medications that modulate (for example suppress) the immune system (other than steroids for acute relapses of MS) (concomitant use of any immunosuppressive/ immunomodulating medication other than steroids for acute relapses) Safety of Ocrevus after other immunosuppressive/immunomodulating disease-modifying MS medications, except for beta interferons and glatiramer acetate (safety of Ocrevus following immunosuppressive/ immunomodulating disease-modifying therapies other than beta interferons and glatiramer acetate Safety of other immunosuppressive/immunomodulating diseasemodifying MS medications once Ocrevus treatment has been stopped (safety of immunosuppressive/ immunomodulating diseasemodifying therapies following Ocrevus) What is known Ocrevus is a long-term treatment for a chronic condition. The clinical trials performed were of a limited duration and that the long-term safety of Ocrevus is being monitored in a number of safety studies. Ocrevus has not been studied when used together with medications that modulate (for example suppress) the immune system (other than steroids for acute relapses of MS), such as chemotherapy. Ocrevus has not been studied when used after other medications that treat MS except for beta interferons and glatiramer acetate There is limited experience in treatment with other medications for MS once Ocrevus treatment has been stopped.

11 VI.2.5 Summary of Risk Minimization Measures by Safety Concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists, and other healthcare professionals with details on how to use the medicine, the risks and recommendations for minimizing them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimization measures. The Swiss Product Information for Ocrevus can be found at This medicine has no additional risk minimization measures. VI.2.6 Planned Post Authorization Development Plan List of Studies in Post Authorization Development Plan Study/activity type, title and category (1-3) Objectives Safety concerns addressed Status Date for submission of interim or final reports Study BN29739: Title: A Phase IIIb, Multicentre, Randomized, Parallel-Group, Open-Label Study To Evaluate The Effects Of Ocrelizumab On Immune Responses In Patients With Relapsing Forms Multiple Sclerosis (Interventional, Category 3) This multicenter, randomized, open-label Phase IIIb study will evaluate the immune response to vaccines (tetanus toxoid, 23- valent pneumococcal polysaccharide vaccine, influenza vaccine, and KLH) after administration of a dose of ocrelizumab in participants with RMS. Impaired immunizati on response Ongoing Primary CSR: Q Final CSR: Q Study BA39732 Title: Multi-Source Surveillance Study of Pregnancy and Infant Outcomes in Ocrelizumab- Exposed Women with Multiple Sclerosis (Non-interventional, Category 3) To estimate the frequency of selected adverse pregnancy outcomes in women with MS exposed to ocrelizumab during the defined exposure window (i.e., spontaneous abortions, stillbirths, elective abortions, and preterm births) To estimate the frequency of selected adverse fetal/neonatal/infant outcomes at birth and up to Use in pregnancy and lactation Protocol synopsis submitted with this RMP Final report: March 2024

12 the first year of life of infants from pregnancies in women with MS exposed to ocrelizumab (i.e., congenital malformations, adverse effects on immune system development [e.g., severe infectious disease in the first year of life], and low birth weight) To compare the frequency of each safety event of interest between ocrelizumab-exposed pregnant women with MS and two comparison cohorts: (a) pregnancies in women with MS who have not been exposed to ocrelizumab (overall, and in two strata: pregnancies exposed to nonocrelizumab DMTs, and pregnancies not exposed to DMTs), and (b) pregnancies in women without MS who have not been exposed to ocrelizumab Study BA39730 Title: Long-Term Surveillance of Ocrelizumab-Treated Patients with Multiple Sclerosis (Non-interventional, Category 3) To assess and characterize the long-term safety data from the use of ocrelizumab in patients with MS. The primary objective is to estimate the event rates of SAEs, including malignancy and infections, following ocrelizumab treatment in patients with MS The secondary objective is: to compare the incidence of each serious safety event between ocrelizumab-exposed patients with MS and patients with MS exposed to other approved DMTs (overall and by individual Long-term safety of ocrelizumab treatment Infections Malignancies including breast cancer PML Safety of ocrelizumab following immunosupp Protocol synopsis submitted with this RMP Interim reports: biannually; summarized in the next PSUR/ PBRER due. The study duration will be 10 years. The final report will be submitted after study end in line with regulatory requirements 12/16

13 DMTs if possible), within the same data source. If sufficient data are available, an exploratory objective of this study is to compare the safety profile of patients with MS exposed to ocrelizumab to the safety profile of patients with MS not exposed to any DMTs. ressive/ immunomod ulating DMTs other than beta interferons and glatiramer acetate. Study WA40404 A Phase IIIb Multicenter, Randomised, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis Later in their Disease Course (category 3) To evaluate the safety and efficacy of ocrelizumab (Ocrevus ) compared with placebo in patients EDSS 3 to 8 using 9HPT as the primary efficacy outcome, and 12 week confirmed disability progression as a key secondary endpoint. Baseline assessment of features characteristic of imaging inflammatory activity (T1 Gd-enhancing MRI lesions) will be undertaken to explore treatment effect in subgroups with different inflammatory profiles. Use in patients between 55 and 65 years old. Use in more disabled patients (EDSS 6.5 to 8) Long-term (5 years or more) safety of ocrelizumab treatment Planned Dec 2024 Monkey Study To assess immunization status of babies born to mother s treated with ocrelizumab Use in pregnancy & lactation Planned Final report Dec 2019 CSR = Clinical Study Report; DMT = disease-modifying therapy; FPI = First Patient In; LPLV = Last Patient Last Visit; OLE = open-label extension; PBRER = Periodic Benefit-Risk Evaluation Report; PSUR = Periodic Safety Update Report; SFU = safety follow-up. 13/16

14 2.6.2 Studies which are a Condition of the Marketing Authorization None of the above studies are conditions of the marketing authorization. 14/16

15 VI.2.7 Summary of Changes to the Risk Management Plan Over Time Major Changes to the Risk Management Plan Over Time Version Date Safety Concerns Comment (At time of authorization dd/mm/yyyy)* 1.1 Assessment completed Important identified risks: Infusion-related reactions Infections Important potential risks: Hypersensitivity reactions Malignancies including breast cancer Impaired immunization response Missing information: Use in pregnancy and lactation Use in pediatric population Use in patients over 55 years old (including elderly) Long-term safety of Ocrevus treatment Concomitant use of any immunosuppressive/ immunomodulating medication other than steroids for acute relapses Safety of Ocrevus following immunosuppressive/ immunomodulating disease-modifying therapies other than beta interferons and glatiramer acetate Safety of immunosuppressive/ immunomodulating disease-modifying therapies following Ocrevus First version of RMP 1.2 Evaluated Two new important potential risks of PML and serious infections related to decrease in immunoglobulin (particularly in patients previously exposed to immunosuppressive /immunomodulatory drugs or with pre-existing hypogammaglobinaemia) has been added. 1.3 Evaluated Removal of studies conducted as PMR for the FDA. Amendment of lay summary as requested in the Day 195 Joint Assessment Report (JAR). Addition of post approval efficacy study to address a question from the CHMP. Updated indication wording for PPMS. Prepared in response to day 180 questions as part of initial MAA. Prepared in response to Day 195 (JAR) as part of initial MAA. 1.4 Pending approval Alignment with propsed SPC and addition of PASS. Prepared in response to Day 195 (JAR) as part of initial MAA. 15/16

16 *Refers to the date of CHMP positive opinion. Note, not all versions of the EU RMP are approved by the CHMP. 16/16