Ocrelizumab

Registered South African indications:

• Relapsing forms of multiple sclerosis (RMS)
• Primary progressive multiple sclerosis (PPMS)

Contraindications

South African recommendations

• Hypersensitivity to ocrelizumab or any of its excipients
• Life threatening infusion reaction to ocrelizumab
• Active hepatitis B virus infection
• Active hepatitis C virus infection
• Active infection (irrespective of pathogen), including active tuberculosis, at the time of a planned infusion of ocrelizumab
• Women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion
• Coadministration with live attenuated vaccines while receiving ocrelizumab

Recommendations in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Current active infection
• Patients in a severely immunocompromised state
• Known active malignancies

Cautions

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment
• Moderate to severe hepatic impairment
• Patients on pre-existing antihypertensive treatment (See additional prescribing points)
• Congestive heart failure (New York Heart Association III & IV)
• Primary progressive multiple sclerosis patients with swallowing difficulties
• Polytherapy with immunosuppressants
• Patients with positive hepatitis B serology (i.e. negative for HBsAg and positive for HB core antibody (HBcAb+))
• Carriers of hepatitis B virus (positive for surface antigen, HBsAg+)
• Known risk factors for malignancy and patients at risk for recurrence of malignancy
• Higher than recommended doses of ocrelizumab
• Other comorbidities
• Immunisation with live or live-attenuated vaccines within 6 weeks prior to initiation of ocrelizumab treatment
• Infants/neonates exposed to ocrelizumab in utero requiring immunisation with live or live-attenuated vaccines
• Initiating ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive therapy after ocrelizumab
• Coadministration with other disease modifying multiple sclerosis therapies
• Coadministration with the chronic use of immunosuppressants/corticosteroids, except for symptomatic treatment of relapses

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Relapsing forms of multiple sclerosis (RMS)
- To suppress relapses and disease progression (clinical and subclinical disease activity)
Primary progressive multiple sclerosis (PPMS)
- To delay disease progression and reduce deterioration in walking speed

Initial dose: 600mg as two separate IV infusions

• IV: 300mg, as an infusion over approx. 2.5hrs; Followed 2 weeks later by a second 300mg, as an infusion over approx. 2.5hrs

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Initiate the infusion at a rate of 30ml/hr. Thereafter, the rate can be increased in 30ml/hr increments every 30 minutes to a maximum of 180ml/hr. Each infusion should be given over approximately 2.5 hours

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Use isotonic 0.9% sodium chloride solution as the infusion vehicle i.e 300mg in 250ml of the infusion vehicle

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Subsequent doses: 600mg as a single IV infusion every 6 months
- Option 1 (approx. 3.5hr infusion)

• IV: 600mg, as an infusion over approx. 3.5hrs, every 6 months

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Initiate the infusion at a rate of 40ml/hr. Thereafter, the rate can be increased in 40ml/hr increments every 30 minutes to a maximum of 200ml/hr. Each infusion should be given over approximately 3.5 hours

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If patients do not experience a serious infusion-related reaction (IRR) with any previous ocrelizumab infusion, a shorter 2 hour infusion can be administered for subsequent doses

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OR
- Option 2 (approx. 2hr infusion)

• IV: 600mg, as an infusion over approx. 2hrs, every 6 months

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Initiate the infusion at a rate of 100ml/hr for the first 15 minutes. Increase the infusion rate to 200ml/hr for the next 15 minutes. Increase the infusion rate to 250ml/hr for the next 30 minutes. Increase the infusion rate to 300ml/hr for the remaining 60 minutes. Each infusion should be given over approximately 2 hours

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Option 1 & 2: Use isotonic 0.9% sodium chloride solution as the infusion vehicle i.e 600mg in 500ml of the infusion vehicle

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Observe the patient for at least 1 hour after the completion of the infusion

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Ocrelizumab is administered as an IV infusion through a dedicated line under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion-related reactions. Ocrelizumab infusions should not be administered as an intravenous push or bolus

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A minimum interval of 5 months should be maintained between each dose of ocrelizumab

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Premedication: 100mg IV methylprednisolone (or an equivalent) approx. 30 minutes prior to each ocrelizumab infusion and an antihistamine (e.g., diphenhydramine) approx. 30-60 minutes prior to each infusion to reduce the frequency and severity of infusion-related reactions; Consider an antipyretic (e.g., paracetamol) approx. 30-60 minutes prior to each infusion

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In the event of a delayed or missed dose, it should be administered as soon as possible; do not wait until the next planned dose. The treatment interval for ocrelizumab should be maintained between doses

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Substitution by any other biological medicine approved for the indication requires the consent of the prescribing medical practitioner

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• Ocrelizumab is a humanised monoclonal antibody of immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier
• There is a limited amount of data from the use of ocrelizumab in pregnant women. Postponing vaccination with live or live-attenuated vaccines should be considered for neonates and infants born to mothers who have been exposed to ocrelizumab in utero. No B cell count data have been collected in neonates and infants exposed to ocrelizumab and the potential duration of B-cell depletion in neonates and infants is unknown
• Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy
• Animal studies (embro-foetal toxicity) do not indicate teratogenic effects. B-cell depletion in utero was detected. Reproductive toxicity was observed in pre- and post-natal development studies
• Ocrelizumab 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 contraception while receiving ocrelizumab and for 12 months after the last infusion of ocrelizumab

Breastfeeding

• Caution; not recommended
• It is unknown whether ocrelizumab/metabolites are excreted in human milk
• Available pharmacodynamic/toxicological data in animals have shown excretion of ocrelizumab in milk
• A risk to neonates and infants cannot be excluded. Women should be advised to discontinue breastfeeding during ocrelizumab therapy

Fertility

• Preclinical data reveal no special hazards for humans based on studies of male and female fertility in cynomologous monkeys

Renal impairment

• Mild: No dose adjustment recommended
  The safety and efficacy of ocrelizumab in patients with renal impairment has not been formally studied. Patients with mild renal impairment were included in clinical trials
• Moderate to severe: Caution; no dose adjustment recommended
  There is no experience in patients with moderate and severe renal impairment. Ocrelizumab is a monoclonal antibody and cleared via catabolism (i.e. breakdown into peptides and amino acids), and a change in dose is not expected to be required for patients with renal impairment

Hepatic impairment

• Mild: No dose adjustment recommended
  The safety and efficacy of ocrelizumab in patients with hepatic impairment has not been formally studied. Patients with mild hepatic impairment were included in clinical trials
• Moderate to severe: Caution; no dose adjustment recommended
  There is no experience with moderate and severe hepatic impairment. Ocrelizumab is a monoclonal antibody and cleared via catabolism (rather than hepatic metabolism), and a change in dose is not expected to be required for patients with hepatic impairment

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Progressive multifocal leukoencephalopathy
  - New onset or worsening of neurological signs or symptoms

Respiratory Disorders

• Upper respiratory tract infection
• Nasopharyngitis
• Sinusitis
• Bronchitis
• Respiratory tract infection
• Influenza
• Cough
• Catarrh

Gastrointestinal Disorders

• Gastroenteritis
• Oral herpes

Hepatobiliary Disorders

• Hepatitis B reactivation
  - Hepatitis
  - Hepatic failure

Genitourinary Disorders

• Genital herpes

Skin and Subcutaneous Tissue Disorders

• Cellulitis

Immune, Blood and Lymphatic System Disorders

• Viral infection
• Herpes zoster
• Herpes simplex
• Neutropenia
• Late onset of neutropenia
• Decreased blood immunoglobulin M
• Decreased blood immunoglobulin G
• Lymphopenia

Sensory Disorders

• Conjunctivitis

Others

• Infusion-related reactions
  - Pruritis
  - Rash
  - Urticaria
  - Erythema
  - Flushing
  - Hypotension
  - Fever
  - Fatigue
  - Headache
  - Dizziness
  - Throat irritation
  - Oropharyngeal pain
  - Dyspnoea
  - Pharyngeal or laryngeal oedema
  - Nausea
  - Tachycardia
• Malignancies (including breast cancers)

• Live vaccines
• Live-attenuated vaccines
• Immunosuppressants (except corticosteroids for symptomatic treatment of relapses)

• Hepatitis B screening (hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) measurements)

Specific cases may require

• Latent infection screening (e.g. tuberculosis) in high-risk populations
• Quantitative serum immunoglobulins

Additional observations

• Infusion reactions (during infusion and for ≥1hr following the end of the infusion)
• Signs or symptoms of
  - Infection
  - Malignancy, including breast cancer screenings
  - Progressive multifocal leukoencephalopathy

Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B cells. CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells. The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in multiple sclerosis is not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The capacity of B-cell reconstitution and preexisting humoral immunity are preserved. In addition, innate immunity and total T-cell numbers are not affected.

Injection (per 10ml) 300mg

• Ocrevus (Roche) originator