Gazyvaro 1,000 mg concentrate for solution for infusion

EMEA/H/C/002799/II/0036.

Submission of final CSR for study GA04753g/GADOLIN to to fulfil the post authorization commitment [MEA] including updates to Product Information and RMP version 5.0.

EMEA/H/C/002799/II/0036.

Submission of final CSR for study GA04753g/GADOLIN to to fulfil the post authorization commitment [MEA] including updates to Product Information and RMP version 5.0.

GAZYVARO, EMEA/H/C/002799/R/0031
Removal of the black triangle statement (additional monitoring) in SmPC and PL

Submission of the final CSR for CLL11/BO21004 in alignment with the phamracovigilance plan for the RMP

MAH licence transfer from RRL (UK) to RRG (GER) - Brexit

Underlined text has been added, text with strike-through deleted.

4.4       Special warnings and precautions for use

[…]

Hypersensitivity reactions including anaphylaxis

Anaphylaxis has been reported in patients treated with Gazyvaro. Hypersensitivity reactions with immediate (e.g.  anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with Gazyvaro. may be difficult to distinguish from IRRs. Hypersensitivity may be difficult to clinically distinguish from infusion related reactions. Hypersensitivity symptoms can occur after previous exposure and very rarely with the first infusion. If a hypersensitivity reaction is suspected during or after an infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion must be stopped and treatment permanently discontinued. Patients with known IgE mediated hypersensitivity to obinutuzumab must not be treated (see section 4.3).

[…]

10.       DATE OF REVISION OF THE TEXT

26 October 2017

Minor editorial changes:

“Infusion related reactions” abbreviated to IRRs

“Hepatitis B virus” abbreviated to HBV 

“Overall survival” abbreviated to OS

“Progression free survival” abbreviated to PFS

“Follicular lymphoma” abbreviated to FL

“Chronic lymphocytic leukaemia” abbreviated to CLL

Underlined text has been added, text with strike-through deleted:

4.1          Therapeutic indications

Chronic Lymphocytic Leukaemia (CLL)

Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (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 follicular lymphoma. (see section 5.1)

Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

4.2          Posology and method of administration

Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available.

Posology

Prophylaxis and premedication for tumour lysis syndrome (TLS)

Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 10⁹/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12‑24 hours prior to start of Gazyvaro infusion as per standard practice (see section 4.4). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.

Prophylaxis and premedication for infusion related reactions (IRRs)

Premedication to reduce the risk of infusion related reactions is outlined in Table 1 and 2 (see also section 4.4). Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.

Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration (see section 4.4).

Table 1 Premedication to be administered before Gazyvaro infusion to reduce the risk of infusion related reactions in patients with CLL and follicular lymphoma FL(see section 4.4)

¹100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone should not be used as it has not been effective in reducing rates of IRR.

² e.g. 1,000 mg acetaminophen/paracetamol

³ e.g. 50 mg diphenhydramine

^4.If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medication if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required.

Table 2 Premedication to be administered before Gazyvaro infusion to reduce the risk of infusion related reactions in patients with FL (see section 4.4)

¹100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone.
Hydrocortisone should not be used as it has not been effective in reducing rates of IRR.

² If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medication if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required.

³² e.g. 1,000 mg acetaminophen/paracetamol

⁴³ e.g. 50 mg diphenhydramine

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil¹)

For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 32.

Cycle 1

The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered over Day 1 and Day 2, (or Day 1 continued), and on Day 8 and Day 15 of the first 28 day treatment cycle.

Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2). If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion. If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day. 

Cycles 2 - 6

The recommended dose of Gazyvaro in combination with chlorambucil is 1,000 mg administered on Day 1 of each cycle.

Table 23               Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days duration for patients with CLL

¹See section 5.1 for information on chlorambucil dose

Duration of treatment

Six treatment cycles, each of 28 day duration.

Delayed or missed doses

If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyvaro should be maintained between doses.

Follicular lymphoma (FL)

For patients with FL, the recommended dose of Gazyvaro in combination with bendamustine chemotherapy is shown in Table 34.

Patients with previously untreated follicular lymphoma

Induction (in combination with chemotherapy²)

Gazyvaro should be administered with chemotherapy as follows:

·             Six 28-day cycles in combination with bendamustine² or,

·             Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyvaro alone or,

·             Eight 21-day cycles in combination with cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone(CVP).

Maintenance

Patients who achieve a complete or partial response to induction treatment with Gazyvaro in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression or for up to 2 years (whichever occurs first).

Patients with follicular lymphoma who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen

Induction (in combination with bendamustine²)

Cycle 1

The recommended dose of Gazyvaro in combination with bendamustine is 1,000 mg administered on Day 1, Day 8 and Day 15 of the first 28 day treatment cycle.

Cycles 2-6

The recommended dose of Gazyvaro should be administered in six 28-day cycles in combination with bendamustine²in combination with bendamustine is 1,000 mg administered on Day 1 of each 28 day treatment cycle.

Maintenance

Patients who achieved a complete or partial responserespond to induction treatment (i.e. the initial 6 treatment cycles) with Gazyvaro in combination with bendamustine or have stable disease should continue to receive Gazyvaro 1,000 mg as single agent maintenance therapy once every 2 months for two 2 years or until disease progression (whichever occurs first).

Table 34                               Follicular lymphoma: Dose of Gazyvaro to be administered during 6 treatment cycles each of 28 days durationinduction treatment, followed by Gazyvaro maintenance treatment for patients with FL

²See section 5.1 for information on bendamustine dose

Duration of treatment

Induction treatment of approximately six months (Ssix treatment cycles of Gazyvaro, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyvaro, each of 21 day duration when combined with CHOP or CVP) followed by maintenance once every two 2 months for two 2 years or until disease progression (whichever occurs first).

Delayed or missed doses

If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose.

If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1. During induction, the planned treatment interval for Gazyvaro should be maintained between doses.

During maintenance, maintain the original dosing schedule for subsequent doses.

Dose modifications during treatment (all indications)

No dose reductions of Gazyvaro are recommended.

For management of symptomatic adverse events (including IRRs), see paragraph below (Management of IRRs or section 4.4).

Special populations

Elderly

No dose adjustment is required in elderly patients (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30‑89 mL/min) (see section 5.2). The safety and efficacy of Gazyvaro has not been established in patients with severe renal impairment (CrCl < 30 mL/min) (see sections 4.8 and 5.2).

Hepatic impairment

The safety and efficacy of Gazyvaro in patients with impaired hepatic function has not been established. No specific dose recommendations can be made.

Paediatric population

The safety and efficacy of Gazyvaro in children and adolescents aged below 18 years has not been established. No data are available.

Method of administration

Gazyvaro is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution (see section 6.6). Gazyvaro infusions should not be administered as an intravenous push or bolus.

For instructions on dilution of Gazyvaro before administration, see section 6.6.

Instructions on the rate of infusion are shown in Tables 4-5-6.

Table 54               Chronic lymphocytic leukaemia: Standard infusion rate in the absence of infusion related reactions/hypersensitivity and recommendations in case an IRR occurred with previous infusion in patients with CLL (in case of infusion related reactions, see “Management of IRRs”)

Table 65               Follicular lymphoma: Standard infusion rates in the absence of infusion related reactions/hypersensitivity and recommendations in case an IRR occurred with previous infusionin patients with FL (in case of infusion related reactions, see “Management of IRRs”)

Management of IRRs (all indications)

Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below (see also section 4.4).

·             Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.

·             Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 45 and 65). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.

·             Grade 1‑2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 54 and 65). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

4.4          Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.

Based on a subgroup analysis in previously untreated follicular lymphoma, 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 (IRRs)

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 severe IRRs (see section 4.8). For management of IRRs see section 4.2 Posology and method of administration.

If the patient experiences an IRR, the infusion should be managed according to the grade of the reaction. For Grade 4 IRRs, the infusion must be stopped and therapy permanently discontinued. For Grade 3 IRRs, the infusion must be temporarily interrupted and appropriate medicine administered to treat the symptoms. For Grade 1‑2 IRRs, the infusion must be slowed down and symptoms treated as appropriate. Upon resolution of symptoms, the infusion can be restarted, except following Grade 4 IRRs, at no more than half the previous rate and, if the patient does not experience the same adverse event with the same severity, the infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose. In CLL patients, if the previous infusion rate was not well tolerated, instructions for the Cycle 1, Day 1 and Day 2 infusion rate should be used for subsequent cycles (see Table 5 in section 4.2).

Patients must not receive further Gazyvaro infusions if they experience:

·             acute life-threatening respiratory symptoms,

·             a Grade 4 (i.e. life threatening) IRR or,

·             a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion).

Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine.

Hypersensitivity reactions including anaphylaxis

Anaphylaxis has been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to distinguish from IRRs. If a hypersensitivity reaction is suspected during infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion must be stopped and treatment permanently discontinued. Patients with known IgE mediated hypersensitivity to obinutuzumab must not be treated (see section 4.3).

Tumour lysis syndrome (TLS)

Tumour lysis syndrome (TLS) has been reported with Gazyvaro. Patients who are considered to be at risk of TLS (e.g. patients with a high tumour burden and/or a high circulating lymphocyte count [> 25 x 10⁹/L] and/or renal impairment [CrCl < 70 mL/min]) should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidate (e.g. rasburicase) starting 12‑24 hours prior to the infusion of Gazyvaro as per standard practice (see section 4.2). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Neutropenia

Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyvaro. Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life-threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should also be considered (see section 4.2). Cases of lLate onset neutropenia (occurring >28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped)  have also been reportedmay occur. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia (see section 4.8).

Thrombocytopenia

Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyvaro. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of thrombocytopenia (see section 4.8). Fatal haemorrhagic events have also been reported in Cycle 1 in patients treated with Gazyvaro. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician. Use of any concomitant therapies which could possibly worsen thrombocytopenia-related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle.

Worsening of pre-existing cardiac conditions

In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.8). These events may occur as part of an IRR and can be fatal. Therefore patients with a history of cardiac disease should be monitored closely. In addition these patients should be hydrated with caution in order to prevent a potential fluid overload.

Infections

Gazyvaro should not be administered in the presence of an active infection and caution should be exercised when considering the use of Gazyvaro in patients with a history of recurring or chronic infections.  Serious bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Gazyvaro therapy. Fatal infections have been reported.

Patients (CLL) with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections (see section 4.8). In the follicular lymphoma studies, a high incidence of infections was observed in all phases of the studies, including follow-up,; with the highest incidence seen in the maintenance phase. During the follow-up phase, Grade 3-5 infections are observed more in patients who received Gazyvaro plus bendamustine in the induction phase.

Hepatitis B reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti‑CD20 antibodies including Gazyvaro (see section 4.8). Hepatitis B virus screening should be performed in all patients before initiation of treatment with Gazyvaro. At a minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B core antibody (HBcAb) status. These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation.

Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with Gazyvaro (see section 4.8). The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as “cortical” (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (cerebrospinal fluid testing for John Cunningham viral DNA). Therapy with Gazyvaro should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML.

Immunisation

The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B- cell recovery.

Exposure in utero to obinutuzumab and vaccination of infants with live virus vaccines

Due to the potential depletion of B- cells in infants of mothers who have been exposed to Gazyvaro during pregnancy, infants should be monitored for B -cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B- cell count has recovered.  The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6).

4.5          Interaction with other medicinal products and other forms of interaction

No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), fludarabine and cyclophosphamide (FC) (fludarabine, cyclophosphamide), 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 drugs 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.

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, or bendamustine, CHOP or CVP may increase the risk of neutropenia (see section 4.4).

4.6          Fertility, pregnancy and lactation

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. Cconcentrations 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).

Because 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).

4.8          Undesirable effects

Summary of the safety profile

The adverse drug reactions (ADRs) described in this section were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the two three pivotal clinical studies,:

·             BO21004/CLL11, (N=781), and : Patients with previously untreated CLL

·             BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL)

·             GAO4753g/GADOLIN, (N=3962): Ppatients with , in previously untreated CLL patients, and indolent Non Hodgkin Lymphoma (iNHL) patients (81.1% 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 different chemotherapeutic agents (chlorambucil for CLL, and with bendamustine, CHOP or CVP followed by Gazyvaro maintenance therapy for iNHL) and as maintenance monotherapy (in iNHL only). The protocol of study studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolleddefined patients with iNHL including FL. as the study population. 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 67 summarises the ADRs 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)

·             and in 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 67 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.

Frequencies are defined as 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) and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Tabulated list of adverse reactions

Table 76               Summary of ADRs reported with a higher incidence (difference of ≥2% versus the comparator arm) in patients^# receiving Gazyvaro + chemotherapy*

In study GAO4753g/GADOLIN, patients in the bendamustine (B)arm received 6 months of induction treatment only, whereas after the induction period, patients in the Gazyvaro plus bendamustine (G+B) arm continued with Gazyvaro maintenance treatment.

During the maintenance period in study GAO4753g/GADOLIN, the most common adverse reactions were cough (15%), upper respiratory infections (12%), neutropenia (11%), sinusitis (10%), diarrhoea (8%), infusion related reactions (8%), nausea (8%), fatigue (8%), bronchitis (7%), arthralgia (7%), pyrexia (6%), nasopharyngitis (6%), and urinary tract infections (6%). The most common Grade 3-5 adverse reactions were neutropenia (10%), and anaemia, febrile neutropenia, thrombocytopenia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1%).

The profile of adverse reactions in the subgroup of patients with FL  was consistent with the overall iNHL population in both studies.

Description of selected adverse reactions

The incidences presented in the following sections if referring to iNHL are the highest incidence of that ADR reported from either pivotal study (BO21223/GALLIUM, GAO4753g/GADOLIN).

Infusion related reactions (IRRs)

Most frequently reported (≥ 5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, pyrexia, vomiting, dyspnea, flushing, hypertension, headache, tachycardia, dyspnoea, dizziness and diarrhoeaand chest discomfort. Respiratory and cardiac symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported (see section 4.4).

Chronic Lymphocytic Leukaemia

The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 65% with the infusion of the first 1,000 mg of Gazyvaro (20% of patients experiencing a Grade 3‑45 IRR, with no fatal events reported). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3‑5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1.

In patients who received the combined recommended measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti-histamine, omission of antihypertensive medication 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 occurred in relatively few patients) were similar before and after mitigation measures were implemented.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

Grade 3-4 IRRs occurred in 123% of patients. In Cycle 1, the overall incidence of IRRs was higher in patients with receiving Gazyvaro plus chemotherapyand bendamustine (G+B) (55%) compared to patients in the comparator armreceiving B alone (42%) (with Grade 3-5 IRRs reported in 9% and 2%, respectively and no fatal events reported). In patients receiving Gazyvaro plus chemotherapy+B, the incidence of IRRs was highest on Day 1  (38%) and gradually decreased on Days 2, 8 and 15 (25%, 7% and 4%, respectively) with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyvaro alone. During Cycle 2, the incidence of IRRs was lower in patients receiving G+B (24%) compared to patients receiving bendamustine (B) alone (32%). Beyond Cycle 1 Tthe incidence of IRRs in subsequent infusions was comparable between the Gazyvaro and the relevant comparator in both arms and decreased with each cycle. IRRs were also observed in 8% of patients during the Gazyvaro maintenance period. Overall, 3% of patients experienced an infusion related reaction leading to discontinuation of Gazyvaro.

Neutropenia and infections

Chronic Lymphocytic Leukaemia

The incidence of neutropenia was higher in the Gazyvaro plus chlorambucil arm (41%) compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3‑5 events reported in 12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of prolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyvaro plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see section 4.4).

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

In the Gazyvaro plus chemotherapy arm, Tthe incidence of Grade 1-4 neutropenia (4850%) was higher in the Gazyvaro plus chemotherapy bendamustine (G+B) arm relative to the comparator armcompared to the bendamustine (B) alone arm (38% and 32%, respectively) with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 7%, respectively. The incidence of infection was 657881% in the Gazyvaro plus chemotherapy +B arm and 56% in the B arm (with Grade 3-5 events reported in 1822% of patients and 17%, respectively, and fatal events reported in 5 patients (3% of patients) in the G+B and 7 patients (4%) in the B arm). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections (see section 4.4).

Cases of prolonged neutropenia (3% in the G+B arm) and late onset neutropenia (7% in the G+B arm) were also reported (See section 4.4).

Thrombocytopenia and haemorrhagic events

Chronic Lymphocytic Leukaemia

The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm (15%) compared to the rituximab plus chlorambucil arm especially during the first cycle. Four percent of patients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyvaro infusion) (see section 4.4). The overall incidence of haemorrhagic events was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however, all of the events in patients treated with Gazyvaro were reported in Cycle 1. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

The incidence of thrombocytopenia was 14%. lower in the Gazyvaro plus bendamustine  (G+B) arm (15%) compared to the bendamustine (B) alone arm (24%). Thrombocytopenia occurred more frequently in Cycle 1 in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 121% and 5% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients; none of the fatal adverse events occurred in Cycle 1.(11% G+B, 10% B) and Grade 3-5 haemorrhagic events (5% G+B, 3%B) was similar in both treatment arms with no fatal events reported.

Special populations

Elderly

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 46% (156 out of 336) of patients with CLL treated with Gazyvaro plus chlorambucil were 75 years or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than those patients < 75 years of age.

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) study in iNHL, patients 65 years or older experienced more serious adverse events and adverse events leading to withdrawal or death than patients < 65 years of age44% (85 out of 194) of patients treated with Gazyvaro plus bendamustine were 65 years or older. No clinically meaningful differences in safety were observed between these patients and younger patients.

Renal impairment

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 27% (90 out of 336) of patients treated with Gazyvaro plus chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than patients with a CrCl ≥ 50 mL/min (see section 4.2, 4.4 and 5.2). Patients with a CrCl < 30 mL/min were excluded from the study (see section 5.1).

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studiesy (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and a small subset of 8% (15 out of 194) of patients treated with Gazyvaro, respectively plus bendamustine, had moderate renal impairment (CrCL < 50 mL/min). These patients experienced more serious adverse events, and adverse events leading to death and adverse events leading to treatment withdrawal than patients with a CrCl ≥ 50 mL/min (see section 4.2 and 5.2). Patients with a CrCl < 40 mL/min were excluded from the studiesy (see section 5.1).

Additional safety information from clinical studies experience

Progressive multifocal leukoencephalopathy (PML)

PML has been reported in patients treated with Gazyvaro (see section 4.4).

Hepatitis B reactivation

Cases of hepatitis B reactivation have been reported in patients treated with Gazyvaro (see section 4.4).

Gastro-Intestinal Perforation

Cases of gastro-intestinal perforation have been reported in patients receiving Gazyvaro, mainly in iNHL. In the pivotal studiesy in iNHL GAO4753g up to 1% of patients experienced gastrointestinal perforation.

Worsening of pre-existing cardiac conditions

Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro (see section 4.4). These events may occur as part of an IRR and can be fatal.

Laboratory abnormalities

Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyvaro.

Reporting of suspected adverse reactions

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 (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

5.1          Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC15

Mechanism of action

Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II anti‑CD20 antibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineering of the Fc part of obinutuzumab results in higher affinity for FcɣRIII receptors on immune effector cells such as natural killer (NK) cells, macrophages and monocytes as compared to non-glycoengineered antibodies.

In nonclinical studies, obinutuzumab induces direct cell death and mediates antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) through recruitment of FcɣRIII positive immune effector cells. In addition, in vivo, obinutuzumab mediates a low degree of complement dependent cytotoxicity (CDC). Compared to Type I antibodies, obinutuzumab, a Type II antibody, is characterised by an enhanced direct cell death induction with a concomitant reduction in CDC at an equivalent dose. Obinutuzumab, as a glycoengineered antibody, is characterised by enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) compared to non-glycoengineered antibodies at an equivalent dose. In animal models obinutuzumab mediates potent B-cell depletion and antitumour efficacy.

In the pivotal clinical study BO21004/CLL11, 91% (40 out of 44) of evaluable patients treated with Gazyvaro were B-cell depleted (defined as CD19+ B- cell counts < 0.07 x 10⁹/L) at the end of treatment period and remained depleted during the first 6 months of follow up. Recovery of B-cells was observed within 12‑18 months of follow up in 35% (14 out of 40) of patients without progressive disease and 13% (5 out of 40) with progressive disease.

Clinical efficacy and safety

Chronic Lymphocytic Leukaemia

A Phase III international, multicentre, open label, randomised, two-stage, three-arm clinical study (BO21004/CLL11) investigating the efficacy and safety of Gazyvaro plus chlorambucil (GClb) compared to rituximab plus chlorambucil (RClb) or chlorambucil (Clb) alone was conducted in patients with previously untreated chronic lymphocytic leukaemia with comorbidities.

Prior to enrolment, patients had to have documented CD20+ CLL, and one or both of the following measures of coexisting medical conditions: comorbidity score (CIRS) of greater than 6 or reduced renal function as measured by CrCl < 70 mL/min. Patients with inadequate liver function (National Cancer Institute – Common Terminology Criteria for Adverse Events Grade 3 liver function tests (AST, ALT > 5 x ULN for > 2 weeks; bilirubin > 3 x ULN) and renal function (CrCl < 30 mL/min) were excluded. Patients with one or more individual organ/system impairment score of 4 as assessed by the CIRS definition, excluding eyes, ears, nose, throat and larynx organ system, were excluded.

A total of 781 patients were randomiszed 2:2:1 to receive Gazyvaro plus chlorambucil, rituximab plus chlorambucil or chlorambucil alone. Stage 1a compared Gazyvaro plus chlorambucil to chlorambucil alone in 356 patients and Stage 2 compared Gazyvaro plus chlorambucil to rituximab plus chlorambucil in 663 patients. Efficacy results are summariszed in Table 78 and in Figures 1‑3.

In the majority of patients, Gazyvaro was given intravenously as a 1,000 mg initial dose administered on Day 1, Day 8 and Day 15 of the first treatment cycle. In order to reduce the rate of infusion related reactions in patients, an amendment was implemented and 140 patients received the first Gazyvaro dose administered over 2 days (Day 1 [100 mg] and Day 2 [900 mg]) (see section 4.2 and 4.4). For each subsequent treatment cycle (Cycles 2 to 6), patients received Gazyvaro 1,000 mg on Day 1 only. Chlorambucil was given orally at 0.5 mg/kg body weight on Day 1 and Day 15 of all treatment cycles (1 to 6).

The demographics data and baseline characteristics were well balanced between the treatment groupsarms. The majority of patients were Caucasian (95%) and male (61%). The median age was 73 years, with 44% being 75 years or older. At baseline, 22% of patients had Binet Stage A, 42% had Binet Stage B and 36% had Binet Stage C.

The median comorbidity score was 8 and 76% of the patients enrolled had a comorbidity score above 6. The median estimated CrCl was 62 mL/min and 66% of all patients had a CrCl < 70 mL/min. Forty-two percent of patients enrolled had both a CrCl < 70 mL/min and a comorbidity score of > 6. Thirty-four percent of patients were enrolled on comorbidity score alone, and 23% of patients were enrolled with only impaired renal function.

The most frequently reported coexisting medical conditions (using a cut off of 30% or higher), in the MedDRA body systems are: Vascular disorders (73%), Cardiac disorders (46%), Gastrointestinal disorders (38%), Metabolism and nutrition disorders (40%), Renal and urinary disorders (38%), Musculoskeletal and connective tissue disorders (33%).

Table 87               Summary of efficacy from BO21004/CLL11 study

IRC: Independent Review Committee; PFS: progression-free survival; HR: Hazard Ratio; CI: Confidence Intervals, MRD: Minimal Residual Disease