Rituximab Vortuxi

Methotrexate (MTX) naïve populations with rheumatoid arthritis

The use of rituximab is not recommended in MTX-naive patients since a favorable benefit risk relationship has not been established

Infusion related reactions

Rituximab is associated with infusion related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators. In RA, most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses.

The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Depending on the severity of the IRR and the required interventions, temporarily or permanently discontinue rituximab. In most cases, the infusion can be resumed at a 50% reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved. Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of rituximab. Since hypotension may occur during rituximab infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the rituximab infusion.

  • Cardiac disorders

    Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with rituximab. Therefore patients with a history of cardiac disease should be monitored closely.

  • Infections

    Based on the mechanism of action of rituximab and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following rituximab therapy. Serious infections, including fatalities, can occur during therapy with rituximab. Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g. hypogammaglobulinaemia. It is recommended that immunoglobulin levels are determined prior to initiating treatment with rituximab. Patients reporting signs and symptoms of infection following rituximab therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment, patients should be re-evaluated for any potential risk for infections.

  • Progressive multifocal leukoencephalopathy (PML)

    Very rare cases of fatal PML have been reported following use of rituximab. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of. If a patient develops PML, the dosing of rituximab must be permanently discontinued.

  • Hepatitis B Infections

    Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in RA patients receiving rituximab. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with rituximab. At minimum this should include HBsAg-status and HBcAb-status. Patients with active hepatitis B disease should not be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

  • Late neutropenia

    Measure blood neutrophils prior to each course of rituximab and regularly up to 6 months after cessation of treatment, and upon signs or symptoms of infection.

  • Skin reactions

    Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported. In case of such an event with a suspected relationship to rituximab, treatment should be permanently discontinued.

  • Immunization

    Physicians should review the patient's vaccination status and follow current immunization guidelines prior to rituximab therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab. The safety of immunization with live viral vaccines following rituximab therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst peripherally B cell depleted. Patients treated with rituximab may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. Should non-live vaccinations be required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to commencing the next course of rituximab.

  • Concomitant/sequential use of other DMARDs in rheumatoid arthritis

    The use of rituximab in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended. There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following rituximab. The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with rituximab, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following rituximab therapy.

  • Malignancy

    Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with rituximab in RA patients, the present data do not seem to suggest any increased risk of malignancy. However, the possible risk for the development of solid tumours cannot be excluded at this time.