Ofatumumab interacts in the following cases:
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.
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 ofatumumab patient who reports the new onset of or changes in pre-existing neurological signs and symptoms. If a diagnosis of PML is suspected ofatumumab should be discontinued and referral to a neurologist should be considered.
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/mm³), 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.
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 ofatumumab. 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 ofatumumab 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. Ofatumumab 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 ofatumumab. 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 ofatumumab, ofatumumab and any concomitant chemotherapy should be interrupted immediately, and appropriate treatment instituted. Insufficient data exist regarding the safety of resuming ofatumumab in patients who develop HBV reactivation. Resumption of ofatumumab 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. 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 (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.
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 ofatumumab therapy and more frequently in patients who develop cytopenias.
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.
There is a limited amount of data from the use of ofatumumab in pregnant women. Ofatumumab may cross the placenta and cause foetal B-cell depletion based on findings from animal studies. No teratogenicity was observed after intravenous administration of ofatumumab to pregnant monkeys during organogenesis.
Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown.
Treatment with ofatumumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.
To help determine the effects of ofatumumab in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications that happen during treatment or within 6 months after the last dose of ofatumumab to the local representative of the marketing authorisation holder, in order to allow monitoring of these patients through the PRegnancy outcomes Intensive Monitoring programme (PRIM). In addition, all adverse pregnancy events should be reported via the national reporting system.
It is unknown whether ofatumumab 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 ofatumumab and for 12 months following treatment.
The use of ofatumumab in women during lactation has not been studied. It is unknown whether ofatumumab is excreted in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards.
Consequently, a risk to the breast-fed child cannot be excluded during this short period. Afterwards, ofatumumab could be used during breast-feeding if clinically needed. However, if the patient was treated with ofatumumab up to the last few months of pregnancy, breast-feeding can be started immediately after birth.
Since ofatumumab may cause foetal B-cell depletion, effective contraception (methods that result in less than 1% pregnancy rates) has to be used during ofatumumab therapy and for 12 months after the last ofatumumab dose. After this period, planning of a pregnancy in relation to the underlying disease, should be evaluated by the treating physician.
Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving ofatumumab and for 6 months after the last administration of ofatumumab.
There are no data on the effect of ofatumumab on human fertility.
Non-clinical data did not indicate potential hazards for humans based on male and female fertility parameters assessed in monkeys.
No studies on the effects of ofatumumab 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.
The overall safety profile of ofatumumab is based on data from 1,168 patients in clinical trials in CLL. 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.
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.
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 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 (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.
The most important and frequently reported adverse reactions are upper respiratory tract infections (39.4%), systemic injection-related reactions (20.6%), injection-site reactions (10.9%) and urinary tract infections (11.9%).
Adverse reactions that have been reported in association with the use of ofatumumab in pivotal RMS clinical studies are listed by MedDRA system organ class in the table below. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on 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).
Tabulated list of adverse reactions:
| Infections and infestations | |
| Πολύ συχνές | Upper respiratory tract infections1 Urinary tract infections2 |
| Common | Oral herpes |
| General disorders and administration site conditions | |
| Very common | Injection-site reactions (local) |
| Injury, poisoning and procedural complications | |
| Very common | Injection-related reactions (systemic) |
| Investigations | |
| Common | Blood immunoglobulin M decreased |
1 Grouping of preferred terms (PTs) was considered for ADR frequency determination and includes the following: nasopharyngitis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, rhinitis, viral upper respiratory infection, tonsillitis, acute sinusitis, pharyngotonsillitis, laryngitis, pharyngitis streptococcal, viral rhinitis, sinusitis bacterial, tonsillitis bacterial, viral pharyngitis, viral tonsillitis, chronic sinusitis, nasal herpes, tracheitis.
2 Grouping of preferred terms (PTs) was considered for ADR frequency determination and includes the following: urinary tract infection, cystitis, escherichia urinary tract infection, asymptomatic bacteriuria, bacteriuria.
In the RMS phase III clinical studies, the overall rate of infections and serious infections in patients treated with ofatumumab was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). Two patients (0.2%) discontinued and 11 patients (1.2%) temporarily interrupted study treatment due to a serious infection.
In these studies, 39.4% of ofatumumab-treated patients experienced upper respiratory tract infections compared to 37.8% of teriflunomide-treated patients. The infections were predominantly mild to moderate and mostly consisted of nasopharyngitis, upper respiratory tract infection and influenza.
In the RMS phase III clinical studies, injection-related reactions (systemic) were reported in 20.6% of patients treated with ofatumumab.
The incidence of injection-related reactions was highest with the first injection (14.4%), decreasing significantly with subsequent injections (4.4% with second, <3% from third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Two (0.2%) ofatumumab-treated MS patients reported serious injection-related reactions but not life-threatening. The most frequently reported symptoms (≥2%) included fever, headache, myalgia, chills and fatigue.
In the RMS phase III clinical studies, injection-site reactions (local) were reported in 10.9% of patients treated with ofatumumab.
Local reactions at the administration site were very common. Injection-site reactions were all mild to moderate in severity and non-serious in nature. The most frequently reported symptoms (≥2%) included erythema, pain, itching and swelling.
During the course of the RMS phase III clinical studies, decrease in mean value of immunoglobulin M (IgM) (30.9% decrease after 48 weeks and 38.8% decrease after 96 weeks) was observed and no association with risk of infections, including serious infections, was shown.
In 14.3% of patients, treatment with ofatumumab resulted in a decrease in IgM that reached a value below 0.34 g/l.
Ofatumumab was associated with a transient decrease of 4.3% in mean immunoglobulin G (IgG) levels after 48 weeks of treatment but an increase of 2.2% after 96 weeks.
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