Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: Novartis Europharm Limited, Frimley Business Park, Camberley GU16 7SR, United Kingdom
Hypersensitivity to ofatumumab or to any of the excipients listed in section 6.1.
Intravenous ofatumumab has been associated with infusion-related reactions. These reactions may result in temporary interruption or withdrawal of treatment. Pre-medication attenuates infusion-related reactions but these may still occur, predominantly during the first infusion. Infusion-related reactions may include, but are not limited to, anaphylactoid events, bronchospasm, cardiac events (e.g. myocardial ischaemia/infarction, bradycardia), chills/rigors, cough, cytokine release syndrome, diarrhoea, dyspnoea, fatigue, flushing, hypertension, hypotension, nausea, pain, pulmonary oedema, pruritus, pyrexia, rash, and urticaria. In rare cases, these reactions may lead to death. Even with pre-medication, severe reactions, including cytokine release syndrome, have been reported following use of ofatumumab. In the event of a severe infusion-related reaction, the infusion of Arzerra must be interrupted immediately and symptomatic treatment instituted (see section 4.2).
If an anaphylactic reaction occurs, Arzerra should be immediately and permanently discontinued and appropriate medical treatment should be initiated.
Infusion-related reactions occur predominantly during the first 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 Arzerra.
In patients with CLL, tumour lysis syndrome (TLS) may occur with use of Arzerra. Risk factors for TLS include a high tumour burden, high concentrations of circulating cells (≥25,000/mm 3 ), hypovolaemia, 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.
Cases of progressive multifocal leukoencephalopathy (PML) resulting in death have been reported in CLL patients receiving cytotoxic pharmacotherapy, including ofatumumab. A diagnosis of PML should be considered in any Arzerra patient who reports the new onset of or changes in pre-existing neurological signs and symptoms. If a diagnosis of PML is suspected Arzerra should be discontinued and referral to a neurologist should be considered.
The safety of, and ability to generate a primary or anamnestic response to, immunisation with live attenuated or inactivated vaccines during treatment with ofatumumab has not been studied. The response to vaccination could be impaired when B-cells are depleted. Due to the risk of infection, administration of live attenuated vaccines should be avoided during and after treatment with ofatumumab, until B-cell counts are normalised. The risks and benefits of vaccinating patients during Arzerra therapy should be considered.
Hepatitis B virus (HBV) infection and reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with medicinal products classified as CD20- directed cytolytic antibodies, including Arzerra. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in those who are hepatitis B core antibody (anti-HBc) positive but HBsAg negative. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e. HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti- HBs] positive).
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e. increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.
All patients should be screened for HBV infection by measuring HBsAg and anti-HBc before initiation of Arzerra treatment. For patients who show evidence of prior (HBsAg negative, anti-HBc positive) hepatitis B infection, physicians with expertise in managing hepatitis B should be consulted regarding monitoring and initiation of HBV antiviral therapy. Arzerra treatment should not be initiated in patients with evidence of current hepatitis B infection (HBsAg positive) until the infection has been adequately treated.
Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs of hepatitis or HBV reactivation during treatment with and for 6-12 months following the last infusion of Arzerra. HBV reactivation has been reported up to 12 months following completion of therapy. Discontinuation of HBV antiviral therapy should be discussed with physicians with expertise in managing hepatitis B.
In patients who develop reactivation of HBV while receiving Arzerra, Arzerra and any concomitant chemotherapy should be interrupted immediately, and appropriate treatment instituted. Insufficient data exist regarding the safety of resuming Arzerra in patients who develop HBV reactivation. Resumption of Arzerra in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B.
Patients with a history of cardiac disease should be monitored closely. Arzerra should be discontinued in patients who experience serious or life-threatening cardiac arrhythmias.
The effect of multiple doses of Arzerra 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 (i.e. >20 milliseconds) were detected. None of the patients had an increase of QTc to >500 msec. A concentration-dependent increase in QTc was not detected. It is recommended that patients have electrolytes such as potassium and magnesium measured prior to and during the administration of ofatumumab. Electrolyte abnormalities should be corrected. The effect of ofatumumab on patients with prolonged QT intervals (e.g. acquired or congenital) is unknown.
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.
Cytopenias, including prolonged and late-onset neutropenia, have been reported during ofatumumab therapy. Complete blood counts, including neutrophil and platelet counts, should be obtained at regular intervals during Arzerra therapy and more frequently in patients who develop cytopenias.
This medicinal product contains 34.8 mg sodium per 300 mg dose, 116 mg sodium per 1000 mg dose and 232 mg sodium per 2000 mg dose. This should be taken into consideration by patients on a controlled sodium diet.
Although limited formal drug-drug interaction data exist for ofatumumab, there are no known clinically significant interactions with other medicinal products. No clinically relevant pharmacokinetic interactions were observed between ofatumumab and fludarabine, cyclophosphamide,bendamustine, chlorambucil, or its active metabolite, phenylacetic acid mustard.
Live attenuated or inactivated vaccine efficacy may be impaired with ofatumumab. Therefore, the concomitant use of these agents with ofatumumab should be avoided. If the coadministration is judged unavoidable, the risks and benefits of vaccinating patients during therapy with ofatumumab should be considered (see section 4.4).
Since ofatumumab may cause foetal B-cell depletion, effective contraception (methods that result in less than 1% pregnancy rates) has to be used during Arzerra therapy and for 12 months after the last Arzerra dose. After this period, planning of a pregnancy in relation to the underlying disease, should be evaluated by the treating physician.
Ofatumumab may cause foetal B-cell depletion based on findings from animal studies and on its mechanism of action (see section 5.1).
There are no adequate and well-controlled studies in pregnant women to inform a product-associated risk. No teratogenicity or maternal toxicity were observed in an animal reproduction study with administration of ofatumumab to pregnant monkeys (see section 5.3). Ofatumumab should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus.
Administration of live vaccines to neonates and infants exposed to ofatumumab in utero should be avoided until B-cell recovery occurs (see sections 4.4 and 4.5).
It is unknown whether Arzerra is excreted in human milk, however human IgG is secreted in human milk. The safe use of ofatumumab in humans during lactation has not been established. The excretion of ofatumumab in milk has not been studied in animals. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Arzerra and for 12 months following treatment.
There are no data on the effects of ofatumumab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.
No studies on the effects of Arzerra on the ability to drive and use machines have been performed.
No detrimental effects on such activities are predicted from the pharmacology of ofatumumab. The clinical status of the patient and the ADR profile of ofatumumab should be borne in mind when considering the patient’s ability to perform tasks that require judgement, motor or cognitive skills (see section 4.8).
The overall safety profile of ofatumumab is based on data from 1,168 patients in clinical trials in CLL (see section 5.1). This includes 643 patients treated with ofatumumab as monotherapy (in patients with relapsed or refractory CLL) and 525 patients treated with ofatumumab in combination with chemotherapy (chlorambucil or bendamustine or fludarabine and cyclophosphamide).
Adverse reactions reported in patients treated with ofatumumab as monotherapy and with ofatumumab in combination with chemotherapy, are listed below by MedDRA body system organ class and by frequency, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Very common: Lower respiratory tract infection (including pneumonia), upper respiratory tract infection
Common: Sepsis (including neutropenic sepsis and septic shock) herpes viral infection, urinary tract infection
Uncommon: Hepatitis B infection and reactivation, progressive multifocal leukoencephalopathy
Very common: Neutropenia, anaemia
Common: Febrile neutropenia, thrombocytopenia, leukopenia
Uncommon: Agranulocytosis, coagulopathy, red cell aplasia, lymphopenia
Common: Hypersensitivity*
Uncommon: Anaphylactic reactions (including anaphylactic shock)*
Common: Headache*
Uncommon: Tumour lysis syndrome
Common: Tachycardia*
Uncommon: Bradycardia*
Common: Hypotension*, hypertension*
Very common: Dyspnoea*, cough*
Common: Bronchospasm*, chest discomfort*, oropharyngeal pain*, nasal congestion*
Uncommon: Pulmonary oedema*, hypoxia*
Very common: Nausea*, diarrhoea*
Uncommon: Small intestinal obstruction
Very common: Rash*
Common: Urticaria*, pruritus*, flushing*
Common: Back pain*
Very common: Pyrexia*, fatigue*
Common: Cytokine release syndrome*, chills (including rigors), hyperhidrosis
Common: Infusion-related reaction*
* These events are likely attributable to ofatumumab in the setting of an infusion-related reaction and typically occur after the start of infusion and within 24 hours after the completion of the infusion (see section 4.4).
Of the 1,168 patients receiving ofatumumab in clinical trials for CLL, the most frequently observed ADRs were infusion-related reactions which occurred in 711 patients (61%) at any time during treatment. The majority of infusion-related reactions were Grade 1 or Grade 2 in severity. Seven percent of patients had ≥Grade 3 infusion-related reactions at any time during treatment. Two percent of the infusion-related reactions led to discontinuation of treatment. There were no fatal infusionrelated reactions (see section 4.4).
Of the 1,168 patients receiving ofatumumab in clinical trials for CLL, 682 patients (58%) experienced an infection. These included bacterial, viral and fungal infections. 268 (23%) of the 1,168 patients experienced ≥Grade 3 infections. 65 (6%) of the 1,168 patients experienced a fatal infection.
Of the 1,168 patients receiving ofatumumab in clinical trials, 420 patients (36%) experienced an adverse event associated with a decreased neutrophil count; 129 (11%) experienced a serious adverse event associated with a decreased neutrophil count.
In the pivotal study for untreated CLL (OMB110911; ofatumumab plus chlorambucil 217 patients, chlorambucil alone 227 patients), prolonged neutropenia (defined as Grade 3 or 4 neutropenia not resolved between 24 and 42 days after last dose of study treatment) was reported in 41 patients (9%) (23 patients [11%] treated with ofatumumab and chlorambucil, 18 patients [8%] treated with chlorambucil alone). Nine patients (4%) treated with ofatumumab and chlorambucil, and three patients treated with chlorambucil alone had late-onset neutropenia (defined as Grade 3 or 4 neutropenia starting at least 42 days after the last treatment). In the pivotal study (OMB110913, ofatumumab plus fludarabine and cyclophosphamide 181 patients; fludarabine and cyclophosphamide 178 patients) in relapsed CLL patients, prolonged neutropenia was reported in 38 (11%) patients (18 patients [10%] treated with ofatumumab in combination with fludarabine and cyclophosphamide compared to 20 patients [11%] in the fludarabine and cyclophosphamide arm). Thirteen (7%) patients treated with ofatumumab in combination with fludarabine and cyclophosphamide, and 5 (3%) patients treated with fludarabine and cyclophosphamide had late-onset neutropenia.
The effect of multiple doses of Arzerra 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 (i.e. >20 milliseconds) were detected. None of the patients had an increase of QTc to >500 msec. A concentration dependent increase in QTc was not detected.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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