OCREVUS (Page 3 of 7)

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)].

5.5 Malignancies

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:

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).

Table 2 Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for OCREVUS and Higher than REBIF
Adverse Reactions Studies 1 and 2
OCREVUS600 mg IVEvery 24 Weeks *(n=825)% REBIF44 mcg SQ3 Times per Week(n=826)%
*
The first dose was given as two separate 300 mg infusions at Weeks 0 and 2.
Upper respiratory tract infections 40 33
Infusion reactions 34 10
Depression 8 7
Lower respiratory tract infections 8 5
Back pain 6 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).

Table 3 Adverse Reactions in Adult Patients with PPMS with an Incidence of at least 5% for OCREVUS and Higher than Placebo
Adverse Reactions Study 3
OCREVUS600 mg IV Every 24 Weeks * Placebo
(n=486)% (n=239)%
*
One dose of OCREVUS (600 mg administered as two 300 mg infusions two weeks apart)
Upper respiratory tract infections 49 43
Infusion reactions 40 26
Skin infections 14 11
Lower respiratory tract infections 10 9
Cough 7 3
Diarrhea 6 5
Edema peripheral 6 5
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)].

Laboratory Abnormalities

Decreased Immunoglobulins

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.

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