Side Effects of Rebif (interferon beta-1a)

Rebif (interferon beta-1a) is a protein produced by recombinant DNA technology using genetically engineered Chinese hamster ovary cells into which the human interferon beta genes have been introduced, used to treat multiple sclerosis (MS). 

Rebif is designed to be identical to interferon beta that is naturally produced by various cells in the body. Rebif has antiviral properties and plays a role in regulating the immune response. The exact mechanism by which Rebif works in the body to treat MS is not known. 

Rebif does not cure MS. Rather, it helps to decrease the number of flare-ups and slows the occurrence of some of the physical disability that commonly occurs in the disease.

Interferon beta-1a, currently in use to treat multiple sclerosis, and interferon alfa-2b are both under investigation as potential treatments for people with COVID-19 coronavirus disease, the deadly respiratory pandemic caused by the SARS-nCoV-2 virus.

Common side effects of Rebif include

• injection site reactions,
• flu-like symptoms,
• headache,
• muscle aches,
• nausea,
• pain,
• fever,
• diarrhea, and
• infections.

Serious side effects of Rebif include

• stomach pain,
• increased liver enzymes,
• blood disorders (including a drop in the number of red blood cells, white blood cells, and platelets),
• seizures,
• suicidal thoughts or actions (tell your doctor if this occurs),
• liver disease, and
• serious allergic and skin reactions.

Drug interactions of Rebif include zidovudine or hydroxyurea, because it may increase the risk of bone marrow suppression. 

Use of Rebif has not been adequately evaluated in pregnant women. Due to the lack of conclusive safety data, Rebif should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unknown if Rebif is excreted in breast milk. As many drugs enter breast milk and can potentially cause harm to the nursing infant, Rebif should be used cautiously in breastfeeding mothers.  

The most common side effects of interferon beta-1a are:

• injection site reactions,
• flu-like symptoms,
• headache,
• muscle aches,
• nausea,
• pain,
• fever,
• diarrhea, and
• infections.

Flu-like symptoms are commonly experienced when patients first start taking interferon beta-1a. These symptoms can be managed with over-the-counter pain and fever reducers, and usually decrease or go away over time.

Stomach pain, an increase in liver enzymes, and blood disorders including a drop in the number of red blood cells, white blood cells, and platelets also may occur.

Interferon beta-1a may also cause other serious side effects including seizures, suicidal thoughts or actions, liver disease, and serious allergic and skin reactions.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Infusion-related reactions
• Severe mucocutaneous reactions
• Hepatitis B reactivation with fulminant hepatitis
• Progressive multifocal leukoencephalopathy
• Tumor lysis syndrome
• Infections
• Cardiovascular adverse reactions
• Renal toxicity
• Bowel obstruction and perforation

Clinical Trials Experience In Lymphoid Malignancies

Because clinical trials are conducted under widely varying conditions, adverse reaction 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 data described below reflect exposure to rituximab in 2,783 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n=356 and n=2,427). The population included 1,180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL.

Most NHL patients received rituximab as an infusion of 375 mg/m² per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received rituximab 375 mg/m² as an initial infusion followed by 500 mg/m² for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of rituximab-based therapy.

The most common adverse reactions of rituximab (incidence ≥25%) observed in clinical trials of patients with NHL were

• infusion-related reactions,
• fever,
• lymphopenia,
• chills,
• infection, and
• asthenia.

The most common adverse reactions of rituximab (incidence ≥25%) observed in clinical trials of patients with CLL were:

• infusion-related reactions and
• neutropenia.

Infusion-Related Reactions

In the majority of patients with NHL, infusion-related reactions consisting of

• fever,
• chills/rigors,
• nausea,
• pruritus,
• angioedema,
• hypotension,
• headache,
• bronchospasm,
• urticaria,
• rash,
• vomiting,
• myalgia,
• dizziness, or
• hypertension occurred during the first rituximab infusion.

Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the rituximab infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion-related reactions was highest during the first infusion (77%) and decreased with each subsequent infusion.

In patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of rituximab at Cycle 2, the incidence of Grade 3-4 infusion-related reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence of Grade 3- 4 infusion-related reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]).

Infections

Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%).

In randomized, controlled studies where rituximab was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received rituximab. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received rituximab.

Cytopenias And Hypogammaglobulinemia

In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included

• lymphopenia (40%),
• neutropenia (6%),
• leukopenia (4%),
• anemia (3%), and
• thrombocytopenia (2%).

The median duration of lymphopenia was 14 days (range, 1-588 days) and of neutropenia was 13 days (range, 2-116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following rituximab therapy occurred during the single-arm studies.

In studies of monotherapy, rituximab-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients.

In CLL trials, the frequency of prolonged neutropenia and late-onset neutropenia was higher in patients treated with rituximab in combination with fludarabine and cyclophosphamide (R-FC) compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3-4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3-4 neutropenia starting at least 42 days after the last treatment dose.

In patients with previously untreated CLL, the frequency of prolonged neutropenia was 8.5% for patients who received R-FC (n=402) and 5.8% for patients who received FC (n=398). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 14.8% of 209 patients who received R-FC and 4.3% of 230 patients who received FC.

For patients with previously treated CLL, the frequency of prolonged neutropenia was 24.8% for patients who received R-FC (n=274) and 19.1% for patients who received FC (n=274). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 38.7% in 160 patients who received R-FC and 13.6% of 147 patients who received FC.

Relapsed Or Refractory, Low-Grade NHL

Adverse reactions presented in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of rituximab administered as a single agent. Most patients received rituximab 375 mg/m² weekly for 4 doses.

Table 1
Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituximab (N=356)^a,b

In these single-arm rituximab studies, bronchiolitis obliterans occurred during and up to 6 months after rituximab infusion.

Previously Untreated, Low-Grade Or Follicular, NHL

In NHL Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone:

• rash (17% vs. 5%),
• cough (15% vs. 6%),
• flushing (14% vs. 3%),
• rigors (10% vs. 2%),
• pruritus (10% vs. 1%),
• neutropenia (8% vs. 3%), and
• chest tightness (7% vs. 1%).

In NHL Study 5, detailed safety data collection was limited to serious adverse reactions, Grade ≥2 infections, and Grade ≥3 adverse reactions. In patients receiving rituximab as single-agent maintenance therapy following rituximab plus chemotherapy, infections were reported more frequently compared to the observation arm (37% vs. 22%).

Grade 3-4 adverse reactions occurring at a higher incidence (≥2%) in the rituximab group were

• infections (4% vs. 1%) and
• neutropenia (4% vs. <1%).

In NHL Study 6, the following adverse reactions were reported more frequently (≥5%) in patients receiving rituximab following CVP compared to patients who received no further therapy:

• fatigue (39% vs. 14%),
• anemia (35% vs. 20%),
• peripheral sensory neuropathy (30% vs. 18%),
• infections (19% vs. 9%),
• pulmonary toxicity (18% vs. 10%),
• hepato-biliary toxicity (17% vs. 7%),
• rash and/or pruritus (17% vs. 5%),
• arthralgia (12% vs. 3%), and
• weight gain (11% vs. 4%).

Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (=2%) in the rituximab arm compared with those who received no further therapy (4% vs. 1%).

DLBCL

In NHL Studies 7 (NCT00003150) and 8, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone:

• pyrexia (56% vs. 46%),
• lung disorder (31% vs. 24%),
• cardiac disorder (29% vs. 21%), and
• chills (13% vs. 4%).

Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

In NHL Study 8, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP).

The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm:

• thrombocytopenia (9% vs. 7%) and
• lung disorder (6% vs. 3%).

Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (NHL Study 8), neutropenia (NHL Studies 8 and 9 (NCT00064116)), and anemia (NHL Study 9).

CLL

The data below reflect exposure to rituximab in combination with fludarabine and cyclophosphamide in 676 patients with CLL in CLL Study 1 (NCT00281918) or CLL Study 2 (NCT00090051). The age range was 30-83 years and 71% were men. Detailed safety data collection in CLL Study 1 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea.

In CLL Study 1, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients:

• infusion-related reactions (9% in R-FC arm),
• neutropenia (30% vs. 19%),
• febrile neutropenia (9% vs. 6%),
• leukopenia (23% vs. 12%), and
• pancytopenia (3% vs. 1%).

In CLL Study 2, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients:

• infusion-related reactions (7% in R-FC arm),
• neutropenia (49% vs. 44%),
• febrile neutropenia (15% vs. 12%),
• thrombocytopenia (11% vs. 9%),
• hypotension (2% vs. 0%), and
• hepatitis B (2% vs. <1%).

Fifty-nine percent of R-FC-treated patients experienced an infusion-related reaction of any severity.

Clinical Trials Experience In Granulomatosis With Polyangiitis (GPA) (Wegener’s Granulomatosis) And Microscopic Polyangiitis (MPA)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice.

Induction Treatment Of Adult Patients With Active GPA/MPA (GPA/MPA Study 1)

The data presented below from GPA/MPA Study 1 (NCT00104299) reflect the experience in 197 adult patients with active GPA and MPA treated with rituximab or cyclophosphamide in a single controlled study, which was conducted in two phases: a 6 month randomized, double-blind, double-dummy, active-controlled remission induction phase and an additional 12 month remission maintenance phase.

In the 6-month remission induction phase, 197 patients with GPA and MPA were randomized to either rituximab 375 mg/m² once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission.

Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission. The primary analysis was at the end of the 6 month remission induction period and the safety results for this period are described below.

Adverse reactions presented below in Table 2 were adverse events which occurred at a rate of greater than or equal to 10% in the rituximab group. This table reflects experience in 99 GPA and MPA patients treated with rituximab, with a total of 47.6 patient-years of observation and 98 GPA and MPA patients treated with cyclophosphamide, with a total of 47.0 patient-years of observation. Infection was the most common category of adverse events reported (47-62%) and is discussed below.

Table 2
Incidence of All Adverse Reactions Occurring in ≥10% of Rituximab-treated Patients with active GPA and MPA in the GPA/MPA Study 1 Up to Month 6*

Infusion-Related Reactions

• Infusion-related reactions in GPA/MPA Study 1 were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators.
• Among the 99 patients treated with rituximab, 12% experienced at least one infusion-related reaction, compared with 11% of the 98 patients in the cyclophosphamide group.
• Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the rituximab group, the proportion of patients experiencing an infusion-related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively.
• Patients were pre-medicated with antihistamine and acetaminophen before each rituximab infusion and were on background oral corticosteroids which may have mitigated or masked an infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion-related reactions.

Infections

In GPA/MPA Study 1, 62% (61/99) of patients in the rituximab group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6.

The most common infections in the rituximab group were

• upper respiratory tract infections,
• urinary tract infections, and
• herpes zoster.

The incidence of serious infections was 11% in the rituximab-treated patients and 10% in the cyclophosphamide treated patients, with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia.

Hypogammaglobulinemia

Hypogammaglobulinemia (IgA, IgG or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with rituximab in GPA/MPA Study 1. At 6 months, in the rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50%, and 46% in the cyclophosphamide group.

Follow Up Treatment Of Adult Patients With GPA/MPA Who Have Achieved Disease Control With Induction Treatment (GPA/MPA Study 2)

In GPA/MPA Study 2 (NCT00748644), an open-label, controlled, clinical study, evaluating the efficacy and safety of non-U.S.-licensed rituximab versus azathioprine as follow up treatment in adult patients with GPA, MPA or renal-limited ANCA-associated vasculitis who had achieved disease control after induction treatment with cyclophosphamide, a total of 57 GPA and MPA patients in disease remission received follow up treatment with two 500 mg intravenous infusions of non-U.S.-licensed rituximab, separated by two weeks on Day 1 and Day 15, followed by a 500 mg intravenous infusion every 6 months for 18 months.

The safety profile was consistent with the safety profile for rituximab in GPA and MPA.

Infusion-Related Reactions

In GPA/MPA Study 2, 7/57 (12%) patients in the non-U.S.-licensed rituximab arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (<4%). One patient had two serious IRRs, two IRRs led to a dose modification, and no IRRs were severe, fatal, or led to withdrawal from the study.

Infections

In GPA/MPA Study 2, 30/57 (53%) patients in the non-U.S.-licensed rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all grade infections was similar between the arms. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the group was mild or moderate bronchitis.

Long-Term, Observational Study With Rituximab In Patients With GPA/MPA (GPA/MPA Study 3)

In a long-term observational safety study (NCT01613599), 97 patients with GPA or MPA received treatment with rituximab (mean of 8 infusions [range 1-28]) for up to 4 years, according to physician standard practice and discretion. Majority of patients received doses ranging from 500 mg to 1,000 mg, approximately every 6 months. The safety profile was consistent with the safety profile for rituximab in GPA and MPA.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing 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 in the studies described below with the incidence of antibodies in other studies or to other rituximab products may be misleading.

Using an ELISA assay, anti-rituximab antibody was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent rituximab. Three of the four patients had an objective clinical response.

A total of 23/99 (23%) rituximab-treated adult patients with GPA and MPA developed anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in rituximabtreated adult patients is unclear.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rituximab. 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.

• Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia.
• Cardiac: fatal cardiac failure.
• Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash.
• Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections.
• Neoplasia: disease progression of Kaposi’s sarcoma.
• Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).
• Gastrointestinal: bowel obstruction and perforation.
• Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.
• Nervous system: Posterior Reversible Encephalopathy Syndrome (PRES)/Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

• Formal drug interaction studies have not been performed with rituximab products.
• In patients with CLL, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide.
• In clinical trials of patients with another indication, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab.