OCREVUS: Package Insert and Label Information (Page 2 of 5)
5.3 Progressive Multifocal Leukoencephalopathy (PML)
Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients with MS treated with OCREVUS in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in OCREVUS-treated patients who had not been treated previously with natalizumab (which has a known association with PML), were not taking any immunosuppressive or immunomodulatory medications associated with the risk of PML prior to or concomitantly with OCREVUS, and did not have any known ongoing systemic medical conditions resulting in compromised immune system function.
JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies.
At the first sign or symptom suggestive of PML, withhold OCREVUS and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis.
It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.
If PML is confirmed, treatment with OCREVUS should be discontinued.
5.4 Reduction in Immunoglobulins
As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with OCREVUS treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during OCREVUS treatment and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent serious infections. Consider discontinuing OCREVUS therapy in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins [see Adverse Reactions (6.1)].
An increased risk of malignancy with OCREVUS may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.
5.6 Immune-Mediated Colitis
Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving OCREVUS in the postmarketing setting. Some cases of colitis were serious, requiring hospitalization, with a few patients requiring surgical intervention. Systemic corticosteroids were required in many of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few weeks to years. Monitor patients for immune-mediated colitis during OCREVUS treatment, and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other gastrointestinal signs and symptoms, occur.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Infusion Reactions [see Warnings and Precautions (5.1)]
- Infections [see Warnings and Precautions (5.2)]
- Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)]
- Reduction in Immunoglobulins [see Warnings and Precautions (5.4)]
- Malignancies [see Warnings and Precautions (5.5)]
- Immune-Mediated Colitis [see Warnings and Precautions (5.6)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of OCREVUS has been evaluated in 1311 patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS).
Adverse Reactions in Patients with Relapsing Forms of MS
In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received OCREVUS 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2) [see Clinical Studies (14.1)]. The overall exposure in the 96-week controlled treatment periods was 1448 patient-years.
The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions. Table 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2).
|Adverse Reactions||Studies 1 and 2|
|OCREVUS600 mg IVEvery 24 Weeks *(n=825)%||REBIF44 mcg SQ3 Times per Week(n=826)%|
|Upper respiratory tract infections||40||33|
|Lower respiratory tract infections||8||5|
|Herpes virus- associated infections||6||4|
|Pain in extremity||5||4|
Adverse Reactions in Patients with Primary Progressive MS
In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of OCREVUS (600 mg of OCREVUS administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously [see Clinical Studies (14.2)]. The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years.
The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections. Table 3 summarizes the adverse reactions that occurred in the PPMS trial (Study 3).
|Adverse Reactions||Study 3|
|OCREVUS600 mg IV Every 24 Weeks *||Placebo|
|Upper respiratory tract infections||49||43|
|Lower respiratory tract infections||10||9|
|Herpes virus associated infections||5||4|
Adverse Reactions in Patients who Received 2-hour Infusions
Study 4 was designed to characterize the safety profile of OCREVUS infusions administered over 2 hours in patients with Relapsing-Remitting Multiple Sclerosis who did not experience a serious infusion reaction with any previous OCREVUS infusion. In this study, the incidence, intensity, and types of symptoms of infusion reactions were consistent with those of infusions administered over 3.5 hours [see Clinical Studies (14.3)].
OCREVUS decreased total immunoglobulins with the greatest decline seen in IgM levels; however, a decrease in IgG levels was associated with an increased rate of serious infections.
In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in OCREVUS-treated patients was 0.5%, 1.5%, and 0.1%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in OCREVUS-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of OCREVUS-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively.
The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of IgG and increased rates of serious infections. The type, severity, latency, duration, and outcome of serious infections observed during episodes of immunoglobulins below LLN were consistent with the overall serious infections observed in patients treated with OCREVUS.
Decreased Neutrophil Levels
In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of OCREVUS-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with OCREVUS and were between LLN — 1.5 × 109 /L and 1.0 × 109 /L. Overall, 1% of the patients in the OCREVUS group had neutrophil counts less than 1.0 × 109 /L and these were not associated with an infection.
As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to OCREVUS with the incidence of antibodies to other products may be misleading.
Patients in MS trials (Study 1, Study 2, and Study 3) were tested at multiple time points (baseline and every 6 months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with OCREVUS, 12 (~1%) tested positive for ADAs, of which 2 patients tested positive for neutralizing antibodies. These data are not adequate to assess the impact of ADAs on the safety and efficacy of OCREVUS.
6.3 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of OCREVUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: Immune-mediated colitis [see Warnings and Precautions (5.6)]
Infections and Infestations: Serious herpes infections [see Warnings and Precautions (5.2)] and progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)]
Skin: Pyoderma gangrenosum
7 DRUG INTERACTIONS
7.1 Immunosuppressive or Immune-Modulating Therapies
The concomitant use of OCREVUS and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with OCREVUS. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating OCREVUS [see Warnings and Precautions (5.2)].
A Phase 3b randomized, open-label study examined the concomitant use of OCREVUS and several non-live vaccines in adults 18-55 years of age with relapsing forms of MS (68 subjects undergoing treatment with OCREVUS at the time of vaccination and 34 subjects not undergoing treatment with OCREVUS at the time of vaccination). Concomitant exposure to OCREVUS attenuated antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide, pneumococcal conjugate vaccines, and seasonal inactivated influenza vaccines. The impact of the observed attenuation on vaccine effectiveness in this patient population is unknown. The safety and effectiveness of live or live-attenuated vaccines administered concomitantly with OCREVUS have not been assessed [see Warnings and Precautions (5.2)].
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