Previously untreated advanced follicular lymphoma (FL)

Active Ingredient: Obinutuzumab

Indication for Obinutuzumab

Population group: only adults (18 years old or older)

Therapeutic intent: Curative procedure

Obinutuzumab in combination with chemotherapy, followed by obinutuzumab maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma (FL).

For this indication, competent medicine agencies globally authorize below treatments:

1,000 mg on Days 1, 8, and 15 of 21- or 28-day cycle 1, followed by 1,000 mg on Day 1 of cycles 2-6 or 2-8, and then 1,000 mg every 2 months for 2 years

For:

Dosage regimens

Regimen A :

Intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 14 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, once every 28 days. This step is repeated 5 times. Afterwards, intravenous, 1,000 milligrams obinutuzumab, once every 2 months, over the duration of 2 years.

Regimen B :

Intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, once every 21 days. This step is repeated 7 times. Afterwards, intravenous, 1,000 milligrams obinutuzumab, once every 2 months, over the duration of 2 years.

Regimen C :

Intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, one dose, over the duration of 7 days. Afterwards, intravenous, 1,000 milligrams obinutuzumab, once every 21 days. This step is repeated 7 times. Afterwards, intravenous, 1,000 milligrams obinutuzumab, once every 2 months, over the duration of 2 years.

Detailed description

For patients with FL, the recommended dose of obinutuzumab in combination with chemotherapy is shown in table below.

<υ>Induction (in combination with chemotherapy²):

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

<υ>Maintenance:

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

Follicular lymphoma: Dose of obinutuzumab to be administered during induction treatment, followed by maintenance treatment:

Cycle	Day of treatment	Dose of Gazyvaro
Cycle 1	Day 1	1,000 mg
	Day 8	1,000 mg
	Day 15	1,000 mg
Cycles 2–6 or 2–8	Day 1	1,000 mg
Maintenance	Every 2 months for 2 years or until disease progression (whichever occurs first)	1,000 mg

Duration of treatment

Induction treatment of approximately six months (six treatment cycles of obinutuzumab, each of 28 day duration when combined with bendamustine, or eight treatment cycles of obinutuzumab, 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 obinutuzumab 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

No dose reductions of obinutuzumab are recommended.

Dosage considerations

Obinutuzumab 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.

Obinutuzumab should be administered at the standard infusion rate in Cycle 1 (see Table 1). In patients who do not experience Grade ≥3 infusion related reactions (IRRs) during Cycle 1, Gazyvaro may be administered as a short (approximately 90 minutes) duration infusion (SDI) from Cycle 2 onwards (see Table 2).

Table 1. Follicular lymphoma: Standard infusion rate and recommendations in case an IRR occurred with previous infusion:

Cycle	Day of treatment	Rate of infusion
		The infusion rate may be escalated provided that the patient can tolerate it. For management of IRRs that occur during the infusion, refer to Management of IRRs.
Cycle 1	Day 1 (1 000 mg)	Administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
	Day 8 (1 000 mg)	If no IRR or if an IRR Grade 1 occurred during the previous infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If the patient experienced an IRR of Grade 2 or higher during the previous infusion administer at 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
	Day 15 (1 000 mg)
Cycles 2-6 or 2–8	Day 1 (1 000 mg)
Maintenance	Every 2 months for 2 years or until disease progression (whichever occurs first)

Τable 2. Follicular lymphoma: Short duration infusion (SDI) rate and recommendations in case an IRR occurred with previous infusion:

Cycle	Day of treatment	Rate of infusion
		For management of IRRs that occur during the infusion, refer to Management of IRRs.
Cycles 2–6 or 2–8	Day 1 (1 000 mg)	If no IRR of Grade ≥3 occurred during Cycle 1: 100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes. If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 IRR occurred during the previous SDI, administer the next obinutuzumab infusion at the standard rate (see Table 1).
Maintenance	Every 2 months for 2 years or until disease progression (whichever occurs first)

Management of IRRs

Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of obinutuzumab as outlined below.

Follicular lymphoma (FL):

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. 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.

IRRs occurring during SDI:

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 not greater than 400 mg/hr. If the patient experiences a second Grade 3 IRR after resuming the infusion, the infusion must be stopped and therapy must be permanently discontinued. If the patient is able to complete the infusion without further Grade 3 IRRs, the next infusion should be given at a rate not higher than the standard rate.
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.

Active ingredient

Obinutuzumab
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. Glycoengineering of the Fc part of obinutuzumab results in higher affinity for FcγRIII receptors on immune effector cells such as natural killer cells, macrophages and monocytes as compared to non-glycoengineered antibodies. Read more about Obinutuzumab

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