Ofatumumab

Registered South African indications:

• Relapsing forms of multiple sclerosis (RMS)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Severely immunocompromised state
• Severe active infection until resolution
• Known active malignancy

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Women of childbearing potential not using effective contraception
• Moderate to severe renal impairment
• Hepatic impairment
• Elderly

Injection-related reactions

• Injection site reaction (local) symptoms observed in clinical studies included erythema, swelling, itching, and pain
• Systemic injection-related reactions (SIRRs) observed in clinical studies occurred predominantly with the first injection
• Symptoms observed include fever, headache, myalgia, chills, and fatigue and were predominantly (99.7%) non-serious and mild to moderate in severity
• There were no life-threatening injection reactions in RMS clinical studies
• Patients should be informed that injection-related reactions generally occur within 24 hours and predominantly following the first injection
• Injection-related reactions can be managed with symptomatic treatment, should they occur
• Additional SIRRs reported in the post-marketing setting include rash, urticaria, dyspnoea, angioedema (e.g., tongue, pharyngeal, or laryngeal swelling), and rare cases reported as anaphylaxis
• Most of the cases were non-serious and occurred with the first injection
• While some cases were serious and resulted in discontinuation of ofatumumab treatment, there were also serious cases where patients were able to continue ofatumumab treatment without further incidents
• Some SIRR symptoms may be clinically indistinguishable from Type 1 acute hypersensitivity reactions (IgE-mediated)
• A hypersensitivity reaction may present with any injection, although typically would not present with the first injection
• For subsequent injections, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction
• Patients with known IgE mediated hypersensitivity to ofatumumab must not be treated with ofatumumab
• Only limited benefit of premedication with steroids, antihistamines, or paracetamol was seen in RMS clinical studies
• Ofatumumab-treated patients who received premedication with methylprednisolone (or an equivalent steroid) experienced fewer symptoms such as fever, myalgia, chills, and nausea
• However, the use of steroid premedication increased the occurrence of flushing, chest discomfort, hypertension, tachycardia, and abdominal pain even in the absence of ofatumumab treatment (i.e., in patients receiving placebo injections). Therefore, use of premedication is not required
• The first injection of ofatumumab should be performed under the guidance of an appropriately trained healthcare professional

Infections

• It is recommended to evaluate the patient’s immune status prior to initiating therapy
• Based on its mode of action, ofatumumab has the potential for an increased risk of infections
• Administration should be delayed in patients with an active infection until the infection is resolved
• Ofatumumab should not be given to patients in a severely immunocompromised state until the condition is resolved
• In RMS clinical studies, the proportion of patients with infections was similar in the ofatumumab and the teriflunomide treatment groups
• In the phase III pivotal clinical studies, 51.6% of ofatumumab treated patients experienced at least one infection, compared to 52.7% of teriflunomide treated patients

Treatment of severely immunocompromised patients

• It is not recommended to use other immunosuppressants concomitantly with ofatumumab except corticosteroids for symptomatic treatment of relapses

Progressive multifocal leukoencephalopathy

• No cases of progressive multifocal leukoencephalopathy (PML) have been reported for ofatumumab in the RMS clinical studies
• However, since John Cunningham (JC) virus infection resulting in PML has been observed in patients treated with anti-CD20 antibodies and other MS therapies, physicians should be vigilant for any clinical symptoms or MRI findings that may be suggestive of PML
• If PML is suspected, treatment with ofatumumab should be suspended until PML has been excluded

Hepatitis B virus reactivation

• No cases of hepatitis B virus (HBV) reactivation were identified in ofatumumab RMS clinical studies
• However, hepatitis B reactivation has occurred in patients treated with anti-CD20 antibodies, which in some cases resulted in fulminant hepatitis, hepatic failure, and death
• Patients with active hepatitis B disease should not be treated with ofatumumab
• HBV screening should be performed in all patients before initiation of treatment with ofatumumab
• As a minimum, screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing
• These can be complemented with other appropriate markers as per local guidelines
• Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult a liver disease expert before the start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation

Vaccinations

• All immunisations should be administered according to immunisation guidelines at least 4 weeks prior to initiation of ofatumumab for live or live attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ofatumumab for inactivated vaccines
• Ofatumumab may interfere with the effectiveness of inactivated vaccines
• The safety of immunisation with live or live attenuated vaccines following ofatumumab therapy has not been studied
• Vaccination with live or live attenuated vaccines is not recommended during treatment and after discontinuation until B cell repletion

Vaccination of infants born to mothers treated with ofatumumab during pregnancy

• In infants of mothers treated with ofatumumab during pregnancy, live or live attenuated vaccines should not be administered before the recovery of B cell counts has been confirmed
• Depletion of B cells in these infants may increase the risks from live or live attenuated vaccines
• Inactivated vaccines may be administered as indicated prior to recovery from B cell depletion, however assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted

Effects on ability to drive and use machines

• Ofatumumab is expected to have no or negligible influence on the ability to drive and use machines

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Women of childbearing potential not using effective contraception
• Moderate to severe renal impairment 
• Hepatic impairment 
• Elderly (>55 years)

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Injection-related reactions

• Patients should be informed that systemic injection-related reactions (SIRRs) could occur, generally within 24 hours and predominantly following the first injection
• Symptoms most frequently observed in RMS clinical studies include fever, headache, myalgia, chills, fatigue, nausea and vomiting and were predominantly (99.8%) mild to moderate in severity
• There were no life-threatening SIRRs reported in RMS clinical studies
• Additional SIRRs reported in the post-marketing setting include rash, urticaria, dyspnoea and angioedema (e.g. tongue, pharyngeal or laryngeal swelling), and rare cases which were reported as anaphylaxis
• While some cases were serious and resulted in discontinuation of ofatumumab treatment, there were also serious cases where patients were able to continue ofatumumab treatment without further incidents
• Some SIRR symptoms may be clinically indistinguishable from Type 1 acute hypersensitivity reactions (IgE-mediated)
• A hypersensitivity reaction may present during any injection, although typically would not present with the first injection
• For subsequent injections, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction
• Patients with known IgE-mediated hypersensitivity to ofatumumab must not be treated with ofatumumab
• Only limited benefit of premedication with steroids was seen in RMS clinical studies
• Injection-related reactions can be managed with symptomatic treatment, should they occur
• Therefore, use of premedication is not required
• Injection site reaction (local) symptoms observed in clinical studies included erythema, swelling, itching and pain
• The first injection should be performed under the guidance of an appropriately trained healthcare professional

Infections

• It is recommended to evaluate the patient's immune status prior to initiating therapy
• Based on its mode of action and available clinical experience, ofatumumab has the potential for an increased risk of infections
• Administration should be delayed in patients with an active infection until the infection is resolved
• Ofatumumab must not be given to patients in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia)

Progressive multifocal leukoencephalopathy

• Since John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML) has been observed in patients treated with anti-CD20 antibodies, other MS therapies, and ofatumumab at substantially higher doses in oncology indications, physicians should be vigilant for medical history of PML and for any clinical symptoms or MRI findings that may be suggestive of PML
• If PML is suspected, treatment with ofatumumab should be suspended until PML has been excluded

Hepatitis B virus reactivation

• Hepatitis B reactivation has occurred in patients treated with anti-CD20 antibodies, which in some cases resulted in fulminant hepatitis, hepatic failure and death
• Patients with active hepatitis B disease should not be treated with ofatumumab
• HBV screening should be performed in all patients before initiation of treatment
• As a minimum, screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing
• These can be complemented with other appropriate markers as per local guidelines
• Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult a liver disease expert before the start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation

Treatment of severely immunocompromised patients

• Patients in a severely immunocompromised state must not be treated until the condition resolves
• It is not recommended to use other immunosuppressants concomitantly with ofatumumab except corticosteroids for symptomatic treatment of relapses

Vaccinations

• All immunisations should be administered according to immunisation guidelines at least 4 weeks prior to initiation of ofatumumab for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ofatumumab for inactivated vaccines
• Ofatumumab may interfere with the effectiveness of inactivated vaccines
• The safety of immunisation with live or live-attenuated vaccines following ofatumumab therapy has not been studied
• Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion
• The median time to B-cell recovery to the lower limit of normal (LLN, defined as 40 cells/µl) or baseline value is 24.6 weeks post treatment discontinuation based on data from phase III studies

Vaccination of infants born to mothers treated with ofatumumab during pregnancy

• In infants of mothers treated with ofatumumab during pregnancy, live or live-attenuated vaccines should not be administered before the recovery of B-cell counts has been confirmed
• Depletion of B cells in these infants may increase the risks from live or live-attenuated vaccines
• Inactivated vaccines may be administered as indicated prior to recovery from B-cell depletion, however assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted

Sodium content

• This medicinal product contains less than 1 mmol sodium (23mg) per dose, that is to say essentially 'sodium-free'

Effects on ability to drive and use machines

• Ofatumumab has no or negligible influence on the ability to drive and use machines

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

South African registered indications and dosages

Relapsing forms of multiple sclerosis (RMS)

• SC: Initial dosing at weeks 0,1 and 2: 20mg; Then week 4 onwards: 20mg, monthly

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Missed doses
If an injection of ofatumumab is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals

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Method of administration
Intended for patient self-administration by subcutaneous (SC) injection. Usual sites for SC injections are abdomen, thigh and upper outer arm
The first injection should be performed under the guidance of a healthcare professional

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Comprehensive instructions for administration are usually provided in the patient information leaflet

Not established for use in children below 18 years

Pregnancy 

South African recommendations

• Caution
• There is a limited amount of data from the use of ofatumumab in pregnant women. Ofatumumab may cross the placenta and cause foetal B-cell depletion based on findings from animal studies. No teratogenicity was observed after intravenous administration of ofatumumab to pregnant monkeys during organogenesis
• Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown
• To help determine the effects of ofatumumab in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications that happen during treatment or within 6 months after the last dose of ofatumumab to the marketing authorisation holder, in order to allow monitoring of these patients through the Pregnancy outcomes Intensive Monitoring program (PRIM)
• Women of childbearing potential should use effective contraception (methods that result in <1% pregnancy rates) while receiving ofatumumab and for 6 months after the last administration of ofatumumab

Recommendations in other jurisdictions

• Caution; not recommended
• There is a limited amount of data from the use of ofatumumab in pregnant women. Ofatumumab may cross the placenta and cause foetal B-cell depletion based on findings from animal studies. No teratogenicity was observed after intravenous administration of ofatumumab to pregnant monkeys during organogenesis
• Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown
• Treatment with ofatumumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus
• To help determine the effects of ofatumumab in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications that happen during treatment or within 6 months after the last dose of ofatumumab to the local representative of the marketing authorisation holder, in order to allow monitoring of these patients through the Pregnancy outcomes Intensive Monitoring programme (PRIM). In addition, all adverse pregnancy events should be reported
• Women of childbearing potential should use effective contraception (methods that result in <1% pregnancy rates) while receiving ofatumumab and for 6 months after the last administration of ofatumumab

Breastfeeding

South African recommendations

• Caution; no information available 
• The use of ofatumumab in women during breastfeeding has not been studied. It is unknown whether ofatumumab is transferred into human milk; however, human IgG is present in human milk. There are no data on the effects of ofatumumab on the breastfed newborn/infant or on milk production. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ofatumumab and any potential adverse effects on the breastfed newborn/infant from ofatumumab

Recommendations in other jurisdictions

• Caution 
• The use of ofatumumab in women during breastfeeding has not been studied. It is unknown whether ofatumumab is excreted in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, a risk to the breastfed child cannot be excluded during this short period. Afterwards, ofatumumab could be used during breastfeeding if clinically needed. However, if the patient was treated with ofatumumab up to the last few months of pregnancy, breastfeeding can be started immediately after birth

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• There are no data on the effect of ofatumumab on human fertility. Non-clinical data did not indicate potential hazards for humans based on male and female fertility parameters assessed in monkeys

Recommendations below are applicable to South Africa and other jurisdictions

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; no dose adjustment recommended 
  No specific studies of ofatumumab in patients with renal impairment have been performed
  Patients with mild renal impairment were included in clinical studies
  There is no experience in patients with moderate and severe renal impairment. However, as ofatumumab is not excreted via urine it is not expected that patients with renal impairment require dose modification

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended 
  No studies of ofatumumab in patients with hepatic impairment have been performed
  Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended 
  No studies have been performed in multiple sclerosis patients >55 years.  Based on the limited data available, no dose adjustment is considered necessary in patients >55 years old

Infections and Infestations

Very common

• Upper respiratory tract infections
  - Nasopharyngitis
  - Influenza
  - Sinusitis, including bacterial 
  - Pharyngitis, including viral and streptococcal  
  - Rhinitis, including viral
  - Viral upper respiratory infection
  - Tonsillitis, including bacterial and viral 
  - Acute sinusitis
  - Pharyngotonsillitis
  - Laryngitis
  - Chronic sinusitis
  - Nasal herpes
  - Tracheitis
• Urinary tract infections
  - Cystitis
  - Escherichia urinary tract infection
  - Asymptomatic bacteriuria
  - Bacteriuria

Common

• Oral herpes

Immune System Disorders

Not known

• Hypersensitivity reactions (reported during post-marketing experience)

General Disorders and Administration Site Conditions

Very common

• Injection-site reactions (local)
  - Erythema
  - Pain
  - Itching
  - Swelling

Injury, Poisoning and Procedural Complications

Very common

• Injection-related reactions (systemic)
  - Fever
  - Headache
  - Myalgia
  - Chills
  - Fatigue
  - Nausea and vomiting

Gastrointestinal Disorders

Common

• Nausea and vomiting

Investigations

• Decreased blood immunoglobulin M

• Vaccines (See warning and precautions)
• Immunosuppressive agents

• Quantitative serum immunoglobulins
• Hepatitis B surface antigen (HBsAg)
• Hepatitis B core antibody (HBcAb)

Specific cases may require

• Hepatitis B markers
• Latent infection screening (e.g. hepatitis, tuberculosis)
• Magnetic resonance imaging (MRI) 

Additional observations

• Signs/symptoms of progressive multifocal leukoencephalopathy (PML) e.g. altered mental status, motor deficits (hemiparesis or monoparesis), limb/gait ataxia, and/or vision disturbances

Ofatumumab is a fully human anti-CD20 monoclonal immunoglobulin G1 (IgG1) antibody with a theoretical average molecular weight of 145kDa. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage. The CD20 molecule is also expressed on a small fraction of activated T cells. A subcutaneous route of administration of ofatumumab and subsequent release/absorption from the tissue allows a gradual interaction with B cells.The binding of ofatumumab to CD20 induces lysis of CD20+ B cells primarily through complement-dependent cytotoxicity (CDC) and, to a lesser extent, through antibody-dependent cell-mediated cytotoxicity (ADCC). Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells. CD20-expressing T cells are also depleted by ofatumumab.

Injection (per 0.4ml) 20mg

• Bonspri (Novartis South Africa) originator