Posology : מינונים

4.2 Posology and method of administration                                                                  4.8 Undesirable effects
Arzerra should be administered under the supervision of a physician experienced in the use of cancer       Summary of the safety profile therapy and in an environment where full resuscitation facilities are immediately available.               The overall safety profile of ofatumumab in CLL (previously untreated and relapsed or refractory) is based on data from 511 patients in clinical trials (see section 5.1). This includes 250 patients Monitoring                                                                                                 treated with ofatumumab alone (in patients with relapsed or refractory CLL) and 261 patients Patients should be closely monitored during administration of ofatumumab for the onset of infusion         treated in combination with an alkylating agent (in patients with previously untreated CLL who reactions, including cytokine release syndrome, particularly during the first infusion.                    are inappropriate for a fludarabine-based therapy).

Pre-medication                                                                                             Tabulated list of adverse reactions Patients should always be pre-medicated 30 minutes to 2 hours prior to Arzerra infusion according          Adverse reactions reported with ofatumumab, either alone or in combination with an alkylating to the following dosing schedules:                                                                         agent, are listed below by MedDRA body system organ class and by frequency.
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Previously untreated CLL:                                                                                  Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); Not known (cannot be estimated from • oral paracetamol (acetaminophen) 1,000 mg (or equivalent), plus                                        available data). Within each frequency grouping, undesirable effects are presented in order of • oral or intravenous antihistamine (diphenhydramine 50 mg or cetirizine 10 mg or equivalent),           decreasing seriousness.
plus
• intravenous corticosteroid (prednisolone 50 mg or equivalent).                                         MedDRA                Very common         Common              Uncommon             Rare System Organ
Following the first and second infusion, if the patient does not experience a severe adverse drug          Class reaction (ADR), pre-medication with a corticosteroid for subsequent infusions may either be reduced or omitted, at the discretion of the physician.                                                    Infections and        Lower respiratory   Sepsis, including                        Hepatitis B Infestations          tract infection,    neutropenic                              infection and Refractory CLL:                                                                                                                  including           sepsis and septic                        reactivation pneumonia,          shock, herpes
• oral paracetamol (acetaminophen) 1,000 mg (or equivalent), plus                                                              upper respiratory   virus infection, • oral or intravenous antihistamine (diphenhydramine 50 mg or cetirizine 10 mg or equivalent),                                 tract infection     urinary tract plus                                                                                                                                            infection • intravenous corticosteroid (prednisolone 100 mg or equivalent).
Blood and             Neutropenia,        Febrile             Agranulocytosis, If the second weekly infusion is completed without a severe ADR, the dose of the corticosteroid            lymphatic system      anaemia             neutropenia,        coagulopathy, may be reduced for infusion numbers 3 through 8, at the discretion of the physician.                       disorders                                 thrombocytopenia,   red cell aplasia, Prior to the ninth infusion (first monthly infusion), patients should receive the full dose of pre-                                                  leukopenia          lymphopenia medication agents described above. If the ninth infusion is completed without a severe ADR, the dose may be reduced to the equivalent of 50 mg prednisolone for subsequent infusions, at the               Immune system                             Anaphylactoid       Anaphylactic discretion of the physician.                                                                               disorders                                 reactions*,         shock* hypersensitivity*
Posology                                                                                                   Metabolism and                                                Tumour lysis nutrition disorders                                           syndrome Previously untreated CLL:
Cardiac disorders                         Tachycardia*        Bradycardia* The recommended dose and schedule is 300 mg on day 1 followed 1 week later by 1,000 mg on day 8 (cycle 1), followed by 1,000 mg on day 1 of subsequent cycles, for a minimum of 3 cycles,            Vascular disorders                        Hypotension*, until best response or a maximum of 12 cycles (every 28 days).                                                                                       hypertension* Respiratory,                              Bronchospasm*,      Pulmonary Best response is a clinical response that did not improve with 3 additional cycles of treatment.
thoracic and                              hypoxia*,           oedema* First infusion                                                                                             mediastinal                               dyspnoea*, chest disorders                                 discomfort*,
The initial rate of the first infusion of Arzerra should be 12 ml/h. During infusion, the rate should                                                pharyngolaryngeal be increased every 30 minutes to a maximum of 400 ml/h (see section 6.6).                                                                            pain*, cough*, nasal congestion*
Subsequent infusions
If the first infusion has been completed without severe infusion related ADRs, the subsequent              Gastrointestinal   Nausea*                Diarrhoea*          Small intestinal infusions can start at a rate of 25 ml/h and should be increased every 30 minutes up to a maximum          disorders                                                     obstruction of 400 ml/h (see section 6.6).                                                                             Skin and           Rash*                  Urticaria*, subcutaneous                              pruritus*,
Refractory CLL:                                                                                            tissue disorders                          flushing* The recommended dose is 300 mg for the first infusion and 2,000 mg for all subsequent infusions.           Musculoskeletal                           Back pain* The infusion schedule is 8 consecutive weekly infusions, followed 4-5 weeks later by 4 consecutive         and connective monthly (i.e., every 4 weeks) infusions.                                                                   tissue disorders General disorders Pyrexia*                 Cytokine release
First and second infusions                                                                                 and administration                         syndrome*, The initial rate of the first and second infusion of Arzerra should be 12 ml/hour. During infusion,        site conditions                            rigors*, chills*, the rate should be increased every 30 minutes to a maximum of 200 ml/hour (see section 6.6).                                                          hyperhidrosis*, fatigue*
Subsequent infusions
*These events are likely attributable to ofatumumab in the setting of an infusion reaction and If the second infusion has been completed without severe infusion related ADRs, the remaining              typically occur after the start of infusion and within 24 hours after the completion of the infusion infusions can start at a rate of 25 ml/hour and should be increased every 30 minutes up to a               (see section 4.4).
maximum of 400 ml/hour (see section 6.6).
Description of selected adverse reactions
Dose modification and reinitiation of therapy for infusion related ADRs – in patients with previously untreated CLL and refractory CLL.                                                                          Infusion reactions Interrupt infusion for infusion related ADRs of any severity. Treatment can be resumed at the discretion   The most frequently observed ADRs in patients receiving Arzerra in clinical trials were infusion- of the treating physician. The following infusion rate modifications can be used as a guide:               related reactions which occurred in 68% (348/511) of patients at any time during treatment. The majority of infusion reactions were Grade 1 or Grade 2 in severity. Eight percent of patients had • In case of a mild or moderate ADR, the infusion should be interrupted and restarted at Grade ≥3 infusion reactions at any time during treatment. Two percent of the infusion reactions half of the infusion rate at the time of interruption, when the patient’s condition is stable.
led to discontinuation of treatment. There were no fatal infusion reactions (see section 4.4).
If the infusion rate had not been increased from the starting rate of 12 ml/hour prior to interrupting due to an ADR, the infusion should be restarted at 12 ml/hour, the standard               Infections starting infusion rate. The infusion rate can continue to be increased according to standard procedures, according to physician discretion and patient tolerance (not to exceed increasing          Of the 511 patients receiving ofatumumab in clinical trials, 300 patients (59%) experienced the rate every 30 minutes).                                                                            an infection. These included bacterial, viral, or fungal infections. One-hundred and four (20%) of the 511 patients experienced ≥ Grade 3 infections. Twenty-eight (5%) of the 511 patients • In case of a severe ADR, the infusion should be interrupted and restarted at 12 ml/hour, when          experienced a fatal infection.
the patient’s condition is stable. The infusion rate can continue to be increased according to standard procedures, according to physician discretion and patient tolerance (not to exceed            Neutropenia increasing the rate every 30 minutes).                                                                 Of the 511 patients receiving ofatumumab in clinical trials, 139 patients (27%) experienced an adverse event associated with a decreased neutrophil count; 118 (23%) of the 511 patients Paediatric population                                                                                      experienced ≥Grade 3 adverse events associated with a decreased neutrophil count. Forty-two Arzerra is not recommended for use in children below 18 years due to insufficient data on safety           (8%) experienced a serious adverse event associated with a decreased neutrophil count.
and/or efficacy.
In the pivotal study for untreated CLL (OMB110911), prolonged neutropenia (defined as Grade 3 or Elderly                                                                                                    4 neutropenia not resolved between 24 and 42 days of last treatment) was reported in 41 patients (23 patients treated with ofatumumab and chlorambucil, 18 patients treated with chlorambucil No substantial differences were seen in safety and efficacy related to age (see section 5.1).
alone). Nine patients treated with ofatumumab and chlorambucil, and three patients treated with Based on available safety and efficacy data in the elderly, no dose adjustment is required (see chlorambucil alone had late onset neutropenia, defined as Grade 3 or 4 neutropenia starting at section 5.2).
least 42 days after the last treatment.
Renal impairment
Cardiovascular
No formal studies of Arzerra in patients with renal impairment have been performed. No dose The effect of multiple doses of Arzerra on the QTc interval was evaluated in a pooled analysis of adjustment is recommended for mild to moderate renal impairment (creatinine clearance >30 three open-label studies in patients with CLL (N = 85). Increases above 5 msec were observed ml/min) (see section 5.2).
in the median/mean QT/QTc intervals in the pooled analysis. No large changes in the mean QTc Hepatic impairment                                                                                         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.
No formal studies of Arzerra in patients with hepatic impairment have been performed. However, patients with hepatic impairment are unlikely to require dose modification (see section 5.2).              Postmarketing Experience Method of administration                                                                                   The following adverse reactions have been identified during post-approval use of Arzerra. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible Arzerra is for intravenous infusion and must be diluted prior to administration. For instructions          to reliably estimate their frequency or establish a causal relationship to drug exposure.
on dilution of the medicinal product before administration, see section 6.6.                               Infusion-related Cardiac Events: Cardiac arrest.
Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.