Obinutuzumab

Obinutuzumab is a recombinant, humanised, glycoengineered Type II anti-CD20 antibody of the IgG1 isotype. It binds the extracellular loop of the CD20 transmembrane antigen on normal and malignant pre-B and mature B lymphocytes, and so depletes B cells. In lymphoid cancers this removes the malignant cells; in lupus nephritis it removes the B cells that drive the autoimmune kidney disease.

Mechanism of Action

• Target: CD20 is found on pre-B and mature B lymphocytes, normal and malignant, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue.
• Direct cell death: as a Type II antibody, obinutuzumab induces direct cell death more strongly, and complement-dependent cytotoxicity less, than Type I antibodies at an equivalent dose. In vivo it mediates only a low degree of complement-dependent cytotoxicity.
• Immune effector cells: glycoengineering of the Fc part gives higher affinity for FcγRIII receptors on natural killer cells, macrophages and monocytes. This enhances antibody-dependent cellular cytotoxicity and phagocytosis compared with non-glycoengineered antibodies at an equivalent dose.
• B-cell depletion: in animal models obinutuzumab produced potent B-cell depletion and antitumour efficacy. In the pivotal CLL study (CLL11), 91% (40 of 44) of evaluable patients were B-cell depleted (CD19-positive B-cell count below 0.07 × 10⁹/L) at the end of treatment and stayed depleted during the first 6 months of follow-up. B cells recovered within 12–18 months in 35% of patients without progressive disease and 13% of those with progressive disease.

Pharmacokinetics

• Absorption: obinutuzumab is given intravenously, so absorption does not apply. After the Cycle 6 Day 1 infusion, population models give a median peak concentration of 465.7 μg/mL in CLL and 539.3 μg/mL in indolent non-Hodgkin lymphoma (iNHL), with AUC over the dosing interval of 8,961 and 10,956 μg·day/mL. In lupus nephritis (LN) at steady state the median peak is 468 μg/mL and the AUC 8,740 μg·day/mL.
• Distribution: the volume of the central compartment is 2.98 L in CLL, 2.97 L in iNHL and 2.22 L in LN, close to serum volume. Distribution is largely restricted to plasma and interstitial fluid.
• Metabolism: not directly studied. Antibodies are cleared mostly by catabolism.
• Elimination: clearance is about 0.11 L/day in CLL and 0.08 L/day in iNHL, with a median elimination half-life of 26.4 days in CLL and 36.8 days in iNHL. In LN, steady-state clearance is about 0.13 L/day and the median half-life 22.4 days. Two parallel pathways clear it: a linear pathway and a non-linear, time-varying one. Early in treatment the non-linear pathway dominates (target-mediated disposition, because many CD20-positive cells remove the antibody), and its role fades as the target cells are bound and depleted.
• Special populations: no dose adjustment is needed by age or in mild to moderate renal impairment (see Administration and Dosage).

• Chronic lymphocytic leukaemia (CLL): in combination with chlorambucil, for adults with previously untreated CLL and with comorbidities that make them unsuitable for full-dose fludarabine-based therapy.
• Follicular lymphoma (FL), previously untreated: in combination with chemotherapy, followed by Gazyvaro maintenance in patients who respond, for patients with previously untreated advanced FL.
• Follicular lymphoma, after rituximab: in combination with bendamustine, followed by Gazyvaro maintenance, for 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): in combination with mycophenolate mofetil (MMF), for adults with active Class III or IV lupus nephritis, with or without concomitant Class V. This is the nephrology use of the medicine.

• Hypersensitivity to obinutuzumab or to any of the excipients.

The most frequent adverse reactions are infusion-related reactions (IRRs), which occur mainly during the first 1,000 mg. The SmPC reports the oncology (CLL and FL) and lupus nephritis safety data separately. The frequencies below are for CLL and indolent non-Hodgkin lymphoma including FL, from the three pivotal studies (CLL11, GALLIUM and GADOLIN), for reactions at least 2% more frequent than with the comparator. Obinutuzumab was given with chlorambucil, bendamustine, CHOP or CVP, so some reactions come partly from the chemotherapy.

Very common (≥1/10): infusion-related reactions; upper respiratory tract infection, sinusitis, urinary tract infection, pneumonia, herpes zoster, nasopharyngitis; neutropenia, thrombocytopenia, anaemia, leukopenia; insomnia; headache; cough; diarrhoea, constipation; alopecia, pruritus; arthralgia, back pain, pain in extremity; pyrexia, asthenia, fatigue.

Common (≥1/100 to <1/10): oral herpes, rhinitis, pharyngitis, lung infection, influenza; squamous cell carcinoma of the skin, basal cell carcinoma; febrile neutropenia; tumour lysis syndrome, hyperuricaemia, hypokalaemia; depression, anxiety; atrial fibrillation; hypertension; nasal congestion, rhinorrhoea, oropharyngeal pain; dyspepsia, haemorrhoids, gastrointestinal perforation; eczema; musculoskeletal chest pain, bone pain; dysuria, urinary incontinence; chest pain; decreased white blood cell and neutrophil counts, increased weight.

Uncommon (≥1/1,000 to <1/100): hepatitis B reactivation; disseminated intravascular coagulation; hypogammaglobulinaemia.

Rare (≥1/10,000 to <1/1,000): cytokine release syndrome.

Not known: progressive multifocal leukoencephalopathy (PML).

The most frequent severe (grade 3–5) reactions are neutropenia, thrombocytopenia and infusion-related reactions. Important serious reactions are severe or life-threatening IRRs and hypersensitivity, tumour lysis syndrome, prolonged or late-onset neutropenia, acute thrombocytopenia with fatal bleeding, disseminated intravascular coagulation, serious infections including hepatitis B reactivation and PML, and cardiac events in patients with heart disease.

No formal interaction studies have been performed, though limited sub-studies were done with bendamustine, CHOP, fludarabine with cyclophosphamide, and chlorambucil. A risk of interaction with other medicines cannot be excluded.

• Pharmacokinetic interactions: obinutuzumab is not a substrate, inhibitor or inducer of cytochrome P450 enzymes, UGT enzymes or transporters such as P-glycoprotein, so no interaction is expected with medicines handled by these systems. It did not change the pharmacokinetics of bendamustine, fludarabine with cyclophosphamide, chlorambucil or the CHOP components, and none of them changed its own.
• Live virus vaccines: not recommended during treatment and until B-cell recovery, because of the immunosuppressive effect of obinutuzumab.
• Chemotherapy: combining obinutuzumab with chlorambucil, bendamustine, CHOP or CVP may increase the risk of neutropenia.
• Antihypertensive medicines: hypotension can occur during infusion. Consider withholding antihypertensives for 12 hours before and throughout each infusion and for the first hour afterwards; in patients at acute risk of hypertensive crisis, weigh the benefits and risks of withholding them.
• Platelet inhibitors and anticoagulants: these may worsen thrombocytopenia-related events, especially in the first cycle.

Gazyvaro should be given under the close supervision of an experienced physician, in an environment where full resuscitation facilities are immediately available. It is given as an intravenous infusion through a dedicated line after dilution (see SmPC section 6.6), never as an intravenous push or bolus. The name and batch number of the product given should be recorded.

Prophylaxis and Premedication

• Tumour lysis syndrome: patients with a high tumour burden, a circulating lymphocyte count above 25 × 10⁹/L, or renal impairment (creatinine clearance below 70 mL/min) are at risk and should receive prophylaxis: adequate hydration and a uricostatic such as allopurinol, or a urate oxidase such as rasburicase, starting 12–24 hours before the infusion. Repeat before each infusion if appropriate.
• Infusion-related reactions in CLL and FL: on Cycle 1 Day 1, an intravenous corticosteroid completed at least 1 hour before the infusion (mandatory in CLL, recommended in FL), plus an oral analgesic/antipyretic such as paracetamol and an antihistamine at least 30 minutes before. In CLL an intravenous corticosteroid is also mandatory on Cycle 1 Day 2. Examples are 100 mg prednisone/prednisolone, 20 mg dexamethasone or 80 mg methylprednisolone; hydrocortisone should not be used because it has not reduced IRR rates.
• Later infusions in CLL and FL: an oral analgesic/antipyretic if the previous infusion caused no IRR; add an antihistamine after a grade 1 or 2 IRR; give an intravenous corticosteroid, analgesic and antihistamine after a grade 3 IRR or when the lymphocyte count before the next treatment is above 25 × 10⁹/L.
• Lupus nephritis: all patients receive intravenous methylprednisolone (80 mg) completed 30–60 minutes before the infusion, an oral analgesic/antipyretic (for example 650–1,000 mg paracetamol) and an antihistamine. From Dose 6 the corticosteroid is given only to patients who had an IRR with the previous infusion.

Recommended Dose

• CLL (with chlorambucil, six 28-day cycles): Cycle 1 is 100 mg on Day 1, 900 mg on Day 2 (or Day 1 continued), then 1,000 mg on Day 8 and on Day 15. Cycles 2–6 are 1,000 mg on Day 1. Two infusion bags (100 mg and 900 mg) are prepared. If the first bag finishes without rate changes or interruptions, the second may be given the same day without repeating premedication, provided time, conditions and supervision allow. If the rate was changed or the infusion interrupted during the first 100 mg, give the second bag the next day.
• FL, previously untreated: with chemotherapy as six 28-day cycles with bendamustine, six 21-day cycles with CHOP followed by 2 further cycles of Gazyvaro alone, or eight 21-day cycles with CVP. Cycle 1 is 1,000 mg on Days 1, 8 and 15, then 1,000 mg on Day 1 of the later cycles. Patients with a complete or partial response then receive 1,000 mg alone every 2 months for 2 years or until progression.
• FL, after rituximab: with bendamustine for six 28-day cycles, using the same 1,000 mg schedule (Days 1, 8 and 15 of Cycle 1, then Day 1 of Cycles 2–6). Patients with a complete or partial response, or stable disease, then receive 1,000 mg every 2 months for 2 years or until progression.
• Lupus nephritis (with mycophenolate mofetil): 1,000 mg intravenously as the initial infusion, then at Week 2, Week 24 and Week 26, and then every 6 months (Dose 5 six months after Dose 4). The condition and response are evaluated at Week 76 and beyond, with a risk-benefit analysis before continuing.

Infusion Rate

• CLL: Cycle 1 Day 1 (100 mg) at 25 mg/hr over 4 hours, without increasing the rate. Day 2 (900 mg) at 50 mg/hr if the previous infusion caused no IRR, increasing by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr; after an IRR start at 25 mg/hr. Later 1,000 mg infusions start at 100 mg/hr (increasing by 100 mg/hr every 30 minutes to 400 mg/hr) if there was no IRR and the final previous rate was 100 mg/hr or faster; after an IRR start at 50 mg/hr.
• FL: Cycle 1 Day 1 at 50 mg/hr, increasing by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr. Later infusions start at 100 mg/hr (increasing by 100 mg/hr every 30 minutes) after no IRR or a grade 1 IRR, and at 50 mg/hr after a grade 2 or higher IRR. Patients without a grade 3 or higher IRR in Cycle 1 may receive a short-duration infusion (about 90 minutes) from Cycle 2: 100 mg/hr for 30 minutes, then 900 mg/hr for about 60 minutes.
• Lupus nephritis: the initial infusion starts at 50 mg/hr and increases by 50 mg/hr every 30 minutes to 400 mg/hr; from Dose 2, 100 mg/hr increasing by 100 mg/hr every 30 minutes to 400 mg/hr. Patients without a grade 3 or higher IRR with the previous infusion may have the short-duration infusion (100 mg/hr for 30 minutes, then 900 mg/hr for about 60 minutes) from Dose 2, with continued premedication.
• After a grade 1–2 IRR with ongoing symptoms, or a grade 3 IRR, during a short-duration infusion, the next infusion is given at the standard rate.

Management of Infusion-Related Reactions

• Grade 4 (life threatening): stop the infusion and discontinue treatment permanently.
• Grade 3 (severe): stop the infusion temporarily and treat the symptoms. When they resolve, restart at no more than half the previous rate and resume the rate escalation if there are no further symptoms. A second grade 3 IRR means stopping the infusion and discontinuing permanently.
• Grade 1–2 (mild to moderate): reduce the rate and treat the symptoms. Continue once they resolve and resume the rate escalation if there are no further symptoms. In lupus nephritis, reduce the rate to half that at the time of the reaction.

Dose Modifications, Delayed and Missed Doses

• No dose reductions of Gazyvaro are recommended.
• If a planned dose is missed, give it as soon as possible without waiting for the next planned dose, and keep the planned interval between doses. In FL, if toxicity before Cycle 1 Day 8 or Day 15 delays treatment, those doses are given after the toxicity resolves and the later visits shift accordingly. During maintenance, keep the original schedule.

Special Populations

• Elderly: no dose adjustment. Safety and efficacy in lupus nephritis above 65 years have not been established.
• Renal impairment: no adjustment in mild to moderate impairment (creatinine clearance 30–89 mL/min). Safety and efficacy in severe impairment (below 30 mL/min) have not been established.
• Hepatic impairment: safety and efficacy have not been established, and no specific dose recommendation can be made.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Infusion-Related Reactions and Hypersensitivity

IRRs were the most frequent adverse reactions, mostly during the first 1,000 mg, and may relate to cytokine release syndrome. They may be clinically indistinguishable from IgE-mediated allergic reactions such as anaphylaxis. Most were mild to moderate and managed by slowing or briefly stopping the first infusion, but severe and life-threatening IRRs have occurred. Risk is higher with a high tumour burden or a circulating lymphocyte count above 25 × 10⁹/L in CLL, with renal impairment (creatinine clearance below 50 mL/min), and with a Cumulative Illness Rating Scale score above 6 together with creatinine clearance below 70 mL/min. No further infusions should be given after acute life-threatening respiratory symptoms, a grade 4 IRR or a second grade 3 IRR. Patients with existing heart or lung disease need careful monitoring during and after the infusion.

Immediate (anaphylaxis) and delayed (serum sickness) hypersensitivity have been reported, rarely with the first infusion. If it is suspected, stop the infusion and discontinue treatment permanently.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported. Patients at risk need the prophylaxis described above and careful monitoring of renal function, potassium and uric acid in the first days. It is treated by correcting electrolyte abnormalities, monitoring renal function and fluid balance, and supportive care including dialysis as indicated.

Neutropenia and Thrombocytopenia

Severe and life-threatening neutropenia, including febrile neutropenia, has been reported. Monitor with regular blood tests until it resolves, consider G-CSF, and consider delaying doses. Antimicrobial prophylaxis is strongly recommended for severe neutropenia lasting more than a week, and antiviral and antifungal prophylaxis should be considered. Late-onset neutropenia (more than 28 days after the end of treatment) or prolonged neutropenia can occur, and renal impairment (creatinine clearance below 50 mL/min) raises the risk.

Severe and life-threatening thrombocytopenia has been seen, including acute thrombocytopenia within 24 hours of an infusion, and fatal haemorrhagic events have been reported in Cycle 1, although a clear link has not been established. Monitor platelets closely, especially in the first cycle, consider delaying doses, and consider platelet inhibitors and anticoagulants. Transfusion is at the treating physician’s discretion.

Coagulation Abnormalities

Disseminated intravascular coagulation, including fatal cases, has been reported. Most cases were non-overt, with changes in platelets and laboratory coagulation parameters 1–2 days after the first infusion that usually resolved within one to two weeks. Monitor suspected cases, and stop Gazyvaro at the first sign of suspected overt DIC.

Cardiac Conditions

In patients with underlying heart disease, arrhythmias (such as atrial fibrillation), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred, sometimes as part of an IRR and sometimes fatally. Monitor these patients closely and hydrate with caution to avoid fluid overload.

Infections, Hepatitis B and PML

Do not give Gazyvaro during an active infection, and take care in patients with recurring or chronic infections. Serious bacterial, fungal and new or reactivated viral infections can occur during and after treatment, and some have been fatal. In CLL, patients with a Cumulative Illness Rating Scale score above 6 and creatinine clearance below 70 mL/min are at higher risk. In FL the highest infection rates were in the maintenance phase.

Hepatitis B reactivation, sometimes with fulminant hepatitis, liver failure and death, can occur with anti-CD20 antibodies. Screen every patient for hepatitis B before treatment (at least HBsAg and HBcAb). Patients with active hepatitis B must not be treated, and those with positive serology should be monitored and managed to prevent reactivation (in oncology, after advice from liver disease experts).

PML has been reported. Consider it in any patient with new or changed neurological signs. Withhold Gazyvaro during investigation (neurologist, MRI, cerebrospinal fluid test for JC virus DNA) and stop permanently if PML is confirmed; consider also reducing or stopping concomitant chemotherapy or immunosuppression. PML was not reported in the placebo-controlled lupus nephritis studies.

Immunisation

Live or attenuated virus vaccines are not recommended during treatment and until B-cell recovery. Infants of mothers exposed to Gazyvaro in pregnancy should be monitored for B-cell depletion, and live vaccines should be postponed until the infant’s B-cell count has recovered; the timing is discussed with the infant’s physician.

Follicular Lymphoma at Low Risk

In previously untreated FL, efficacy in FLIPI low-risk (0–1) patients is currently inconclusive. The choice of therapy for these patients should weigh the safety profile of Gazyvaro plus chemotherapy and the patient’s situation.

Lupus Nephritis

The warnings on infections, hepatitis B screening, neutropenia, IRRs, PML and immunisation apply in lupus nephritis as well. For IRRs, corticosteroid premedication is mandatory (see above). Safety and efficacy have not been established above 65 years or in severe renal impairment (creatinine clearance below 30 mL/min).

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for 18 months after it.
• Pregnancy: there are no data in pregnant women. A study in cynomolgus monkeys showed no embryofoetal toxicity or teratogenic effects but complete depletion of B lymphocytes in the offspring, which recovered with immune function restored within 6 months of birth. The antibody appears to cross the placenta, and B-cell depletion may be expected in exposed infants. Gazyvaro should not be given to pregnant women unless the benefit outweighs the risk.
• Breastfeeding: obinutuzumab is secreted in animal milk and human IgG is secreted in human milk. Women should stop breastfeeding during treatment and for 18 months after the last dose.
• Fertility: no specific animal studies of the effect on fertility have been performed.

Effect on Driving

Gazyvaro has no or negligible influence on the ability to drive and use machines. IRRs are very common with the first infusion, and patients with infusion-related symptoms should not drive or use machines until they pass.

Store the vial in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Keep the cold chain unbroken during transport and handling.

After dilution in sodium chloride 9 mg/mL (0.9%) solution at 0.4–20 mg/mL, the infusion solution is chemically and physically stable for 72 hours at 2–8 °C, followed by 48 hours (including infusion time) at up to 30 °C. From a microbiological point of view, use the prepared infusion immediately. Otherwise in-use storage times and conditions are the user’s responsibility and would normally not be longer than 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Each pack holds one 50 mL clear Type I glass vial with a butyl rubber stopper, containing 40 mL of concentrate.

3 years for the unopened vial. For the diluted solution, see Storage Conditions.

Prescription only (Rx), a medicinal product subject to restricted medical prescription (Annex II B), initiated and supervised by an experienced physician. Gazyvaro is given as an intravenous infusion where full resuscitation facilities are available, so it is supplied to the hospital or clinic that administers it, by cold-chain delivery at 2–8 °C.