Gazyvaro

HOS-096824 · has-adverse-reaction-information · PDF-Seite 18

Undesirable effects are presented separately for the Oncology (Chronic lymphocytic leukaemia and Follicular lymphoma), and for the Lupus nephritis indications. 18 Chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL) Summary of the safety profile The adverse drug reactions (ADRs) from clinical trials were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the three pivotal clinical studies: • BO21004/CLL11 (N=781): Patients with previously untreated CLL • BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL) • GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen. These trials investigated Gazyvaro in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by Gazyvaro maintenance therapy for iNHL. The studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolled patients with iNHL including FL. Therefore, in order to provide the most comprehensive safety information, the analysis of ADRs presented in the following has been performed on the entire study population (i.e. iNHL). Table 10 summarises all ADRs including those of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of ≥ 2%) compared to the relevant comparator arm in at least one pivotal study in: • Patients with CLL receiving Gazyvaro plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11) • Patients with previously untreated iNHL receiving Gazyvaro plus chemotherapy (bendamustine, CHOP, CVP) followed by Gazyvaro maintenance in patients achieving a response, compared to rituximab plus chemotherapy followed by rituximab maintenance in patients achieving a response (study BO21223/GALLIUM) • Patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen receiving Gazyvaro plus bendamustine, followed by Gazyvaro maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN) The incidences presented in Table 10 (all grades and Grades 3-

Auszug; vollständigen Abschnitt im Original lesen.

HOS-096820 · has-contraindication-information · PDF-Seite 12

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096819 · has-indication-information · PDF-Seite 2

Chronic lymphocytic leukaemia (CLL) Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy (see section 5.1). Follicular lymphoma (FL) Gazyvaro in combination with chemotherapy followed by Gazyvaro maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced FL (see section 5.1) Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen. Lupus nephritis (LN) Gazyvaro in combination with mycophenolate mofetil (MMF) is indicated for the treatment of adult patients with active Class III or IV, with or without concomitant Class V, lupus nephritis (LN).

HOS-096822 · has-interaction-information · PDF-Seite 17

No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP, fludarabine and cyclophosphamide (FC), and chlorambucil. A risk for interactions with other concomitantly used medicinal products cannot be excluded. Pharmacokinetic interactions Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with medicinal products known to be metabolised by these enzyme systems. Co-administration with Gazyvaro had no effect on the pharmacokinetics of bendamustine, FC, chlorambucil or the individual components of CHOP. In addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyvaro. 17 Pharmacodynamic interactions Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery because of the immunosuppressive effect of obinutuzumab (see section 4.4). The combination of obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia (see section 4.4).

HOS-096823 · has-pregnancy-information · PDF-Seite 18

Women of childbearing potential Women of childbearing potential must use effective contraception during and for 18 months after treatment with Gazyvaro. Pregnancy A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B-lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta (see section 5.3). There are no data from the use of obinutuzumab in pregnant women. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk. In case of exposure during pregnancy, depletion of B-cells may be expected in infants due to the pharmacological properties of the product. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to Gazyvaro during pregnancy until the infant’s B-cell levels are within normal ranges (see section 4.4). Breast-feeding Animal studies have shown secretion of obinutuzumab in breast milk (see section 5.3). Since human immunoglobulin G (IgG) is secreted in human milk and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breast-feeding during Gazyvaro therapy and for 18 months after the last dose of Gazyvaro. Fertility No specific studies in animals have been performed to evaluate the effect of obinutuzumab on fertility. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies in cynomolgus monkeys (see section 5.3).

HOS-096821 · has-warning-information · PDF-Seite 12

Traceability In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded. Special warnings and precautions are presented separately for the Oncology (Chronic lymphocytic leukaemia and Follicular lymphoma), and for the Lupus nephritis indications. Chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL) Based on a subgroup analysis in previously untreated FL, the efficacy in FLIPI low risk (0-1) patients is currently inconclusive (see section 5.1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyvaro plus chemotherapy and the patient-specific situation. Infusion related reactions The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1 000 mg. IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti-histamine, omission of antihypertensive medicine in the morning of the first infusion, and the Cycle 1 Day 1 dose administered over 2 days) as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidence and severity of infusion related symptoms decreased substantially after the first 1 000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyvaro (see section 4.8). In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported. IRRs may be clinically indistinguishable from immunoglobulin E (IgE) mediated allergic reactions (e.g. anaphylaxis). Patients with a high tumour burden and/or high circulating lymphocyte count in CLL [> 25 x 109/L] may be at increased risk of severe IRRs. Patients with renal impairment (CrCl < 50 mL/min) and patients with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including se

Auszug; vollständigen Abschnitt im Original lesen.