In the USA, ofatumumab is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the EU, ofatumumab is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. Ofatumumab is also approved for first-line use in Russia.
In more than 50 countries worldwide, ofatumumab is indicated as monotherapy for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.
Ofatumumab is being developed under a co-development and collaboration agreement between Genmab and GSK.
Arzerra is a trademark of the GSK group of companies.
Important Safety Information for ofatumumab (Arzerra) The overall safety profile of ofatumumab in CLL (previously untreated and relapsed or refractory) is based on data from more than 500 patients treated alone or in combination with other therapies in clinical trials.
The most common undesirable effects for ofatumumab include adverse events associated with infusion reactions, cytopenias (neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia) and infections (lower respiratory tract infection, including pneumonia, upper respiratory tract infection, sepsis, including neutropenic sepsis and septic shock, herpes virus infection, urinary tract infection).
Contraindications: Hypersensitivity to ofatumumab or to any of the excipients.
Special warnings and precautions for use of ofatumumab are summarized as follows: Infusion reactions Ofatumumab has been associated with infusion reactions. These reactions may result in temporary interruption or withdrawal of treatment or death. Pre-medications attenuate infusion reactions but these may still occur, predominantly during the first infusion. Infusion reactions may include, but are not limited to, anaphylactic reactions, bronchospasm, cardiac events (eg myocardial ischemia / infarction, bradycardia), chills/rigors, cough, cytokine release syndrome, diarrhea, dyspnoea, fatigue, flushing, hypertension, hypotension, nausea, pain, pulmonary edema, pruritus, pyrexia, rash, and urticaria. Even with pre-medication, severe reactions, including cytokine release syndrome, have been reported following ofatumumab use. In cases of severe infusion reaction, the infusion of ofatumumab must be interrupted immediately and symptomatic treatment instituted (see Dosage and Administration for changes to infusion rates following infusion reactions).
Infusion reactions occur more frequently on the first day of infusion and tend to decrease with subsequent infusions. Patients with a history of decreased pulmonary function may be at a greater risk for pulmonary complications from severe reactions and should be monitored closely during infusion of ofatumumab.
Tumor lysis syndrome In patients with CLL, tumor lysis syndrome (TLS) may occur with use of ofatumumab. Risk factors for TLS include a high tumor burden, high concentrations of circulating cells (= 25,000/mm3), hypovolemia, renal insufficiency, elevated pre-treatment uric acid levels and elevated lactate dehydrogenase levels. Management of TLS includes correction of electrolyte abnormalities, monitoring of renal function, maintenance of fluid balance and supportive care.
Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) and death has been reported in CLL patients receiving cytotoxic pharmacotherapy, including ofatumumab. If a diagnosis of PML is suspected, ofatumumab should be discontinued and referral to a neurologist should be considered.
Immunizations The safety of, and ability to generate a primary or anamnestic response to, immunization with live attenuated or inactivated vaccines during treatment with ofatumumab has not been studied.
Hepatitis B Hepatitis B virus (HBV) infection and reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with drugs classified as CD20-directed cytolytic antibodies, including ofatumumab. All patients should be screened for HBV infection before initiation of ofatumumab treatment, patients previously exposed to HBV should be followed closely in consultation with an expert in this disease. Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs of hepatitis or HBV reactivation.
Cardiovascular Patients with a history of cardiac disease should be monitored closely. Ofatumumab should be discontinued in patients who experience serious or life-threatening cardiac arrhythmias.
The effect of multiple doses of ofatumumab on the QTc interval was evaluated in a pooled analysis of three open-label studies in patients with CLL (N=85). Increases above 5 msec were observed in the median/mean QT/QTc intervals in the pooled analysis. No large changes in the mean QTc interval (ie, >20 milliseconds) were detected.
Bowel obstruction Bowel obstruction has been reported in patients receiving anti-CD20 monoclonal antibody therapy, including ofatumumab. Patients who present with abdominal pain, especially early in the course of ofatumumab therapy, should be evaluated and appropriate treatment instituted.