Gazyva

/ Roche

Obinutuzumab should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available.
Prophylaxis for tumour lysis syndrome (TLS): Prophylaxis with adequate hydration and administration of uricostatics (e.g. allopurinol) starting 12-24 hours prior to start of therapy is recommended for patients with high circulating lymphocyte count (> 25 x 109/L) to reduce the risk of tumour lysis syndrome.
Prophylaxis and premedication for infusion related reactions (IRRs):  Premedication to reduce the risk of infusion related reactions is outlined in Table 1 at doctor’s leaflet. Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1 at doctor’s leaflet). Premedication for subsequent infusions and other premedication should be administered as described at doctor’s leaflet.
Hypotension, as a symptom of IRRs, may occur during Obinutuzumab intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Obinutuzumab infusion and for the first hour after administration.

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil): 
For patients with CLL the recommended dose of Gazyva in combination with chlorambucil is shown in Table 2 at doctor’s leaflet.
Cycle 1: The recommended dose of Obinutuzumab 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 to 6: The recommended dose of Obinutuzumab is 1,000 mg administered on 1^st Day.
Duration of treatment: Six treatment cycles, each of 28 day duration.
Delayed or missed doses: If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyva should be maintained between
doses.

Follicular lymphoma:
For patients with FL, the recommended dose of Gazyva in combination with chemotherapy is shown in Table 3 at doctor’s leaflet.
Patients with previously untreated follicular lymphoma:
Induction (in combination with chemotherapy): Gazyva should be administered with chemotherapy as follows:
– Six 28-day cycles in combination with bendamustine or,
– Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP), followed by 2 additional cycles of Gazyva 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 Gazyva in combination with chemotherapy (CHOP or CVP or bendamustine) should continue to receive Gazyva 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (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 bendamustine): Gazyva should be administered in six 28-day cycles in combination with bendamustine.
Maintenance: Patients who achieved a complete or partial response to induction treatment (i.e. the initial 6 treatment cycles) with Gazyva in combination with bendamustine or have stable disease should continue to receive Gazyva 1,000 mg as single agent maintenance therapy once every 2 months for 2 years or until disease progression (whichever occurs first).
Duration of treatment: Induction treatment of approximately six months (six treatment cycles of Gazyva, each of 28 day duration when combined with bendamustine, or eight treatment cycles of Gazyva, each of 21 day duration when combined with CHOP or CVP) followed by maintenance once every 2 months for 2 years or until disease progression (whichever occurs first).
Delayed or missed doses: If a planned dose of Gazyva 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 maintenance, maintain the original dosing schedule for subsequent doses.
Dose modifications during treatment (all indications): No dose reductions of Gazyva are recommended.
For management of symptomatic adverse events (including IRRs), see prescribing information.
Elderly: No dose adjustment is required in elderly patients. See prescribing information for full details.
Renal impairment: No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30-89 mL/min). The safety and efficacy of Gazyva has not been established in patients with severe renal impairment (CrCl < 30 mL/min).
Hepatic impairment: The safety and efficacy of Obinutuzumab in patients with impaired hepatic function has not been established. No specific dose recommendations can be made.
Paediatric population: The safety and efficacy of Obinutuzumab in children and adolescents aged below 18 years has not been established. No data are available.
Method of administration: This drug is for intravenous use. It should be given as an intravenous infusion through a dedicated line after dilution. Obinutuzumab infusions should not be administered as an intravenous push or bolus.

Management of IRRs (all indications):
Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Obinutuzumab as outlined below.
– 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 4 and 5 at doctor’s leaflet). 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 4 and 5 at doctor’s leaflet). 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.
For full details see prescribing information.

Obinutuzumab in combination with Chlorambucil, is indicated for the treatment of patients with previously untreated Chronic Lymphocytic Leukemia (CLL).
Gazyva in combination with chemotherapy, followed by Gazyva maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma.
Gazyva in combination with bendamustine followed by Gazyva monotherapy 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 a rituximab-containing regimen.

Hypersensitivity to the active substance or to any of the excipients.

Infusion related reactions: Patients must not receive further Obinutuzumab infusions if they experience: Acute life -threatening respiratory symptoms. A Grade 4 (i.e. life threatening) IRR.  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 Obinutuzumab intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Obinutuzumab 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.
Tumour lysis syndrome (TLS): Tumour lysis syndrome (TLS) has been reported with Obinutuzumab.
Hypersensitivity reactions including anaphylaxis:Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness)
have been reported in patients treated with Obinutuzumab. 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.
Hematological disorders: Thrombocytopenia, Neutropenia.
Progressive multifocal leukoencephalopathy (PML): Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with obinutuzumab. The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations.
Infections: Obinutuzumab should not be administered in the presence of an active infection and caution should be exercised when considering the use of obinutuzumab 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 Obinutuzumab  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.
Immunisation: The safety of immunisation with live or attenuated viral vaccines following obinutuzumab therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B cell recovery.
For full details see prescribing information.

Very Common: Upper respiratory tract infection, sinusitis, urinary tract infection,
pneumonia, herpes zoster, Neutropenia, thrombocytopenia, anaemia, leukopenia, Headache, Insomnia, Cough, Diarrhoea, constipation, Alopecia, pruritus, Arthralgia, back pain, Pyrexia, Asthenia, IRR’s.
For full details see prescribing information.

No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyva 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 drugs known to be metabolised by these enzyme systems.
Co-administration with Gazyva 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 Gazyva.
Pharmacodynamic interactions: Vaccination with live virus vaccines is not recommended during treatment and until B cell recovery because of the immunosuppressive effect of obinutuzumab. The combination of obinutuzumab with chlorambucil may increase neutropenia.

Pregnancy: Women of childbearing potential have to use effective contraception during and for 18 months after treatment with Obinutuzumab.
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 Gazyva during pregnancy until the infant’s B-cell levels are within normal ranges.
Lactation: Animal studies have shown secretion of obinutuzumab in breast milk.  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 Gazyva therapy and for 18 months after the last dose of Gazyva.
See prescribing information for full details.

No experience with overdose is available from human clinical studies. In clinical studies with Obinutuzumab, doses ranging from 50 mg up to and including 2,000 mg per infusion have been administered. The incidence and intensity of adverse reactions reported in these studies did not appear to be dose dependent.
Patients who experience overdose should have immediate interruption or reduction of their infusion and be closely supervised. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B cell depleted.

This drug has no or negligible influence on the ability to drive and use machines. IRRs are very common during the first infusion of Obinutuzumab, and patients experiencing infusion related symptoms should be advised not to drive or use machines until symptoms abate.
Storage: Store in a refrigerator (2°C-8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions after dilution of the medicinal product.