Obinutuzumab

Registered South African indications:

• Chronic lymphocytic leukaemia (CLL)
  - In combination with chlorambucil for the treatment of patients with previously untreated CLL
• Follicular lymphoma (FL)
  - In combination with chemotherapy, followed by obinutuzumab maintenance for the treatment of patients with previously untreated FL 
  - In combination with bendamustine followed by obinutuzumab maintenance for the treatment of patients with FL who did not respond to, or who progressed during or after treatment with rituximab or a rituximab-containing regimen

Contraindications 

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Active infections 
• Active hepatitis B infections (See additional prescribing points) 
• Coadministration with live attenuated vaccines

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African recommendations

• Women of childbearing potential and for 18 months following treatment with obinutuzumab
• Severe renal impairment (CrCl≤30ml/min)
• Hepatic impairment
• Elderly (≥75 years old)
• Risk factors for infusion-related reactions (See additional prescribing points)
  - High tumour burden
  - High circulating lymphocyte count in CLL (>25 x 10⁹/l)
• Pre-existing cardiac conditions
  - Underlying or history of cardiac disease
• Pre-existing pulmonary conditions
• Patients at acute risk of hypertensive crisis (See additional prescribing points)
• Risk factors for tumour lysis syndrome (See additional prescribing points)
  - High tumour burden
  - High circulating lymphocyte count (>25 x10⁹/l)
  - Renal impairment (CrCl<70ml/min)
• Positive hepatitis B serology (See additional prescribing points)
• History of recurring or chronic infections
• Pre-existing neurologic manifestations
• Coadministration with therapies which could worsen thrombocytopenia-related events
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Women of childbearing potential and for 18 months following treatment with obinutuzumab
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min)
• Hepatic impairment
• Elderly (≥75 years old)
• FLIPI low risk (0-1) patients
• Risk factors for infusion-related reactions (See additional prescribing points)
  - High tumour burden
  - High circulating lymphocyte count in CLL (>25x10⁹/l)
  - CrCl<50ml/min
  - Both cumulative illness rating scale (CIRS)>6 and CrCl<70ml/min
• Pre-existing cardiac conditions
  - Underlying or history of cardiac disease 
• Pre-existing pulmonary conditions
• Patients at acute risk of hypertensive crisis (See additional prescribing points)
• Risk factors for tumour lysis syndrome (See additional prescribing points)
  - High tumour burden
  - High circulating lymphocyte count (>25x10⁹/l)
  - CrCl<70ml/min
• Risk factors for neutropenia and thrombocytopenia
  - CrCl<50ml/min
• Presence of an active infection
• History of recurring or chronic infections
• Risk factors for infection, including severe infections
  - Both cumulative illness rating scale (CIRS)>6 and CrCl<70ml/min
• Active hepatitis B disease (See additional prescribing points)
• Positive hepatitis B serology (See additional prescribing points) 
• Pre-existing neurologic manifestations
• Coadministration with therapies which could worsen thrombocytopenia-related events 
• Coadministration with chlorambucil, bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CVP (cyclophosphamide, vincristine, prednisone/prednisolone/methylprednisolone) (See additional prescribing points)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inf

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Used for the treatment of

• Chronic lymphocytic leukaemia (CLL) (Additional agent required)
  - In combination with chlorambucil for the treatment of patients with previously untreated CLL
• Follicular lymphoma (FL) (Additional agent required)
  - In combination with chemotherapy, followed by obinutuzumab maintenance therapy in patients with previously untreated FL
  - In combination with bendamustine followed by obinutuzumab maintenance for the treatment of patients with FL who did not respond to, or who progressed during or after treatment with rituximab or a rituximab-containing regimen

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Consult specialist for dosages and regimens

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Should be administered as an intravenous infusion through a dedicated line in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced medical practitioner

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Should not be administered as an intravenous push or bolus

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Substitution of obinutuzumab with any other biological medicinal product requires the consent of the prescribing medical practitioner

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Indications and dosages registered in other jurisdictions

Used for the treatment of

• Chronic lymphocytic leukaemia (CLL) (Additional agent required)
  - In combination with chlorambucil for the treatment of patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy
• Follicular lymphoma (FL) (Additional agent required)
  - In combination with chemotherapy, followed by obinutuzumab maintenance therapy in patients achieving a response, for the treatment of previously untreated advanced FL
  - In combination with bendamustine followed by obinutuzumab maintenance for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen

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Consult specialist for dosages and regimens

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

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Should be administered as an intravenous infusion through a dedicated line after dilution and should not be administered as an intravenous push or bolus 2

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus
• Women of childbearing potential should use effective contraception and for 18 months following treatment with obinutuzumab
• Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to obinutuzumab during pregnancy until the infants B-cell levels are within normal ranges (See additional prescribing points)
• No studies in pregnant women have been performed. 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. Furthermore, the serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta

Recommendations in other jurisdictions

• Caution
• A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B-lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Serum concentrations of obinutuzumab in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that obinutuzumab crosses the placenta
• There are no data from the use of obinutuzumab in pregnant women. Obinutuzumab 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 obinutuzumab during pregnancy until the infant's B-cell levels are within normal ranges (See additional prescribing points)
• Women of childbearing potential must use effective contraception during and for 18 months after treatment

Breastfeeding

South African recommendations

• Contraindicated 
• Since human IgG is secreted in human milk, and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breastfeeding during obinutuzumab therapy and for 18 months after the last dose
• Animal studies have shown excretion of obinutuzumab in breast milk

Recommendations in other jurisdictions

• Caution; not recommended
• 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 breastfeeding during obinutuzumab therapy and for 18 months after the last dose of obinutuzumab

Fertility

South African recommendations

• 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
• To date, no safety-related concern regarding male reproductive functions or contraception has been reported

Recommendations in other jurisdictions

• 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

Renal Impairment

South African recommendations

• Mild to moderate (CrCl>30ml/min): No dose adjustment recommended
• Severe (CrCl≤30ml/min): Caution; no information available

Recommendations in other jurisdictions

• Mild to moderate (CrCl≥30-89ml/min): No dose adjustment recommended
• Severe (CrCl<30ml/min): Caution; no information available

Hepatic Impairment

• Caution; no information available

Elderly

• Caution; no dose adjustment recommended
  In the pivotal CLL study, patients ≥75 years old experienced more serious adverse events and adverse events leading to death than patients <75 years of age

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Depression
• Anxiety 
• Headache
• Fatigue 
• Progressive multifocal leukoencephalopathy
  - Muscular weakness
  - Paralysis
  - Sensory disturbances
  - Cerebellar symptoms
  - Visual field defects
  - Aphasia
  - Visual-spatial disorientation

Cardiovascular Disorders

• Arrhythmias
  - Atrial fibrillation
  - Tachyarrhythmia
• Angina pectoris
• Acute coronary syndrome
• Myocardial infarction
• Heart failure
• Hypertension
• Chest pain

Respiratory Disorders

• Upper respiratory tract infection
• Sinusitis
• Pneumonia
• Bronchitis
• Nasopharyngitis
• Rhinitis
• Pharyngitis
• Lung infection
• Influenza
• Dyspnoea
• Cough
• Nasal congestion
• Rhinorrhoea
• Oropharyngeal pain

Gastrointestinal Disorders

• Oral herpes
• Diarrhoea
• Nausea and vomiting
• Constipation
• Dyspepsia
• Haemorrhoids
• Gastrointestinal perforation

Hepatobiliary Disorders

• Hepatitis B reactivation
  - Fulminant hepatitis
  - Hepatic failure
  - Death
• Elevated hepatic enzymes
  - Aspartate aminotransferase (AST)
  - Alanine aminotransferase (ALT)
  - Alkaline phosphatase

Genitourinary Disorders

• Urinary tract infection
• Dysuria
• Urinary incontinence

Endocrine and Metabolic Disorders

• Tumour lysis syndrome
• Hyperuricaemia
• Hypokalaemia
• Increased weight

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Pain in extremity
• Musculoskeletal chest pain
• Bone pain

Skin and Subcutaneous Tissue Disorders

• Squamous cell carcinoma of skin
• Basal cell carcinoma
• Alopecia
• Pruritus
• Eczema
• Rash

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Anaphylaxis
  - Serum sickness
• Herpes zoster
• Bacterial or fungal infections
• New or reactivated viral infections
• Neutropenia
  - Febrile neutropenia
• Thrombocytopenia
• Anaemia
• Leukopenia
• Disseminated intravascular coagulation
• Sepsis
• Decreased white blood cell count 
• Decreased neutrophil count
• Fever
• Infusion-related reactions
  - Acute life-threatening respiratory symptoms
  - Nausea and vomiting
  - Diarrhoea
  - Headache
  - Dizziness
  - Fatigue
  - Chills
  - Fever
  - Hypotension
  - Flushing
  - Hypertension
  - Tachycardia
  - Dyspnoea
  - Chest discomfort
  - Bronchospasm
  - Larynx and throat irritation
  - Wheezing
  - Laryngeal oedema
  - Atrial fibrillation
• Cytokine release syndrome
• B-cell depletion (in infants born to mothers exposed to obinutuzumab)

• Live or attenuated viral vaccines (See additional prescribing points)
• Platelet inhibitors
• Anticoagulants

• Full blood count with differential
• Renal function
• Electrolytes
• Uric acid levels 
• Hepatitis B virus (HBV) screening (See additional prescribers points) 
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Brain magnetic resonance imaging
• Lumbar puncture 
• Coagulation parameters
• Platelet counts

Additional observations

• Fluid status
• Signs of hepatitis or active hepatitis B infection
• Signs or symptoms of
  - Bleeding episodes due to thrombocytopenia
  - Infusion reaction
  - Hypersensitivity
  - Infection
  - Tumor lysis syndrome
  - Bleeding and thrombosis
• Signs or symptoms of progressive multifocal leukoencephalopathy
  - Focal neurologic deficits (hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits)
• Neurologist evaluation

Traceability

• 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

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

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 obinutuzumab 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

Hypertensive patients

• Hypotension may occur during obinutuzumab intravenous infusions. Therefore, withholding 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 antihypertensive medicine

Hepatitis B reactivation

• HBV screening should be performed in all patients before initiation of treatment with obinutuzumab. See monitoring section for recommended tests
• These can be complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not be treated with obinutuzumab
• Patients with positive hepatitis B serology should consult hepatic disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation

Pharmacodynamic interactions (Recommendations in other jurisdictions) 

• The combination of obinutuzumab with chlorambucil, bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CVP (cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone) may increase the risk of neutropenia

Pharmacokinetic interactions

• Coadministration with obinutuzumab had no effect on the pharmacokinetics of bendamustine, fludarabine and cyclophosphamide (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 obinutuzumab

Infusion-related reactions (IRRs)

• The most frequently observed adverse drug reactions (ADRs) in patients receiving obinutuzumab were IRRs, which occurred predominantly during infusion of the first 1000mg
• IRRs may be related to cytokine release syndrome which has also been reported in obinutuzumab 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), 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
• The incidence and severity of infusion-related symptoms decreased substantially after the first 1000mg was infused, with most patients having no IRRs during subsequent administrations of obinutuzumab
• 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 [>25x10⁹/l] may be at increased risk of severe IRRs
• Patients with renal impairment (CrCl<50ml/min) and patients with both Cumulative Illness Rating Scale (CIRS)>6 and CrCl<70ml/min are more at risk of IRRs, including severe IRRs
• Patients must not receive further obinutuzumab 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)

Tumour lysis syndrome (TLS)

• TLS has been reported with obinutuzumab. 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 [>25x10⁹/l] and/or renal impairment [CrCl<70ml/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 obinutuzumab as per standard practice
• Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate
• 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

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 induced direct cell death and mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) through recruitment of FcɣRIII positive immune effector cells. In vivo, obinutuzumab mediates a low degree of complement-dependent cytotoxicity (CDC). Compared to Type I antibodies, obinutuzumab, a Type II antibody, is characterized 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 ADCC and ADCP compared to non-glycoengineered antibodies at an equivalent dose. In animal models, obinutuzumab mediates potent B-cell depletion and antitumour efficacy.

Infusion (per 40ml) 1000mg

• Gazyva (Roche) originator