Alemtuzumab

Registered South African indications:

• Chronic lymphocytic leukaemia (30mg/ml)
• Highly active relapsing remitting multiple sclerosis (RRMS) (10mg/ml)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Human immunodeficiency virus (HIV) infection
• Severe active infection (until complete resolution)
• Uncontrolled hypertension
• History of arterial dissection of the cervicocephalic arteries
• History of stroke
• History of angina pectoris or myocardial infarction
• Known coagulopathy
• Concomitant autoimmune diseases (besides multiple sclerosis)
• Coadministration with antiplatelet or anticoagulant therapy

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Porphyria
• Women of reproductive potential
• Inactive disease
• Stable on current therapy
• History of thyroid disorders
• History of hypertension
• History of bleeding disorders
• Ischemic heart disease or risk factors thereof
• Active or latent tuberculosis
• Ingestion of uncooked or undercooked meats, soft cheeses and unpasteurized dairy products 2 weeks prior to, during, and for at least one month after alemtuzumab infusion
• Active or chronic hepatitis B virus infection
• Active or chronic hepatitis C virus infection
• Hepatitis B virus and/or hepatitis C virus carriers
• Pre-existing and/or an on-going malignancy
• Immunisation 6 weeks prior to treatment with alemtuzumab
• Live vaccines post-alemtuzumab therapy
• Chickenpox naïve patients or without vaccination against varicella zoster virus (VZV)
• Non multiple sclerosis patients
  - With latent infections when alemtuzumab is used at higher and and more frequent doses than used in MS
  - Previously treated with potentially cardiotoxic agents
• Electrolyte disturbances
• History of autoimmune conditions
• History of infusion-related reactions
• Infections and infestations
• Coadministration with or following antineoplastic or immunosuppressive therapies

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

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

10mg/ml

• Highly active relapsing remitting multiple sclerosis (RMMS) (as a single disease modifying therapy)
  - Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT)
  - Patients with rapidly evolving severe RMMS defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI

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Alemtuzumab treatment should only be initiated and supervised by a neurologist experienced in the treatment of patients with multiple sclerosis (MS) in a hospital with ready access to intensive care

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Specialists and equipment required for the timely diagnosis and management of adverse reactions, especially myocardial ischaemia and myocardial infarction, cerebrovascular adverse reactions, autoimmune conditions, and infections, should be available

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Resources for the management of cytokine release syndrome, hypersensitivity and/or anaphylactic reactions should be available

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Patients treated with alemtuzumab must be given the patient alert card and patient guide and be informed about the risks of alemtuzumab

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Consult specialist for dosages and regimens

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See pre-treatment recommendation in Additional Prescribing Points

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30mg/ml: There is no information available regarding international manufacturer recommendations 

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South African manufacturer recommendations

Used for the treatment of

30mg/ml

• Chronic lymphocytic leukaemia
  - In patients who have been treated with alkylating agents and who have failed to achieve a complete or partial response or who have achieved only a short remission (<6 months) following fludarabine phosphate therapy

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Alemtuzumab should be administered under the supervision of a physician experienced in the use of cancer therapy

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Patients should be pre-medicated with an appropriate antihistamine and analgesic prior to the first dose, at each escalation, and prior to subsequent infusions, as clinically indicated

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Antibiotics and antivirals should be administered routinely to all patients throughout and following treatment

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Consult specialist for dosages and regimens

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10mg/ml

• Highly active relapsing remitting multiple sclerosis (RMMS) (as a single disease modifying therapy)
  - Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT)
  - Patients with rapidly evolving severe RMMS defined by 2 or more disabling relapses in one year, and with 1 or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI

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Administer alemtuzumab in a setting in which equipment and personnel are available to appropriately manage anaphylaxis, serious infusion reactions, myocardial ischaemia, myocardial infarction, and cerebrovascular adverse reactions

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Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution
• There is a limited amount of data from the use of alemtuzumab in pregnant women. Alemtuzumab should be administered during pregnancy only if the potential benefit justifies the potential risk to the foetus
• Human immunoglobulin G is known to cross the placental barrier; alemtuzumab may cross the placental barrier as well and thus potentially pose a risk to the foetus. Animal studies have shown reproductive toxicity. It is not known whether alemtuzumab can cause foetal harm when administered to pregnant women or whether it can affect reproductive capacity
• Thyroid disease poses special risks in women who are pregnant. Without treatment of hypothyroidism during pregnancy, there is an increased risk for miscarriage and foetal effects such as mental retardation and dwarfism. In mothers with Graves' disease, maternal thyroid-stimulating hormone receptor antibodies can be transferred to a developing foetus and can cause transient neonatal Graves' disease
• Women of childbearing potential: Serum concentrations were low or undetectable within approximately 30 days following each treatment course. Therefore, women of childbearing potential have to use effective contraception when receiving a course of treatment with alemtuzumab and up to 4 months after each course of treatment

Breastfeeding

• Caution; not recommended
• Alemtuzumab was detected in the milk and offspring of lactating female mice. It is unknown whether alemtuzumab is excreted in human milk. A risk to the breastfeeding newborn/ infant cannot be excluded
• Therefore, breastfeeding should be discontinued during each course of treatment with alemtuzumab and for 4 months following the last infusion of each treatment course. However, benefits of conferred immunity through breastmilk may outweigh the risks of potential exposure to alemtuzumab for the breastfeeding newborn/ infant

Fertility

• There are no adequate clinical safety data on the effect of alemtuzumab on fertility. In a sub-study in 13 male alemtuzumab-treated patients (treated with either 12mg or 24mg), there was no evidence of aspermia, azoospermia, consistently depressed sperm count, motility disorders or an increase in sperm morphological abnormalities
• CD52 is known to be present in human and rodent reproductive tissues. Animal data have shown effects on fertility in humanised mice, however, a potential impact on human fertility during the period of exposure is unknown based on the available data

Renal Impairment

• Caution; no information available

Hepatic Impairment

• Caution; no information available

Elderly

• Caution; no information available

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Due to the increased risk of infections on alemtuzumab therapy, infections may trigger acute porphyric attacks, therefore monitoring of signs and symptoms of infection and or symptoms of a porphyric attack is recommended. Nausea and vomiting may be possibly porphyrinogenic through reduction in carbohydrate intake

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Anxiety
• Depression
• Headache
  - Tension headache
• Dizziness
• Hypoaesthesia
• Paraesthesia
• Tremor
• Dysgeusia
• Migraine
• Sensory disturbance
• Hyperaesthesia
• Haemorrhagic stroke
• Cervicocephalic arterial dissection
• Multiple sclerosis replase
• Progressive multifocal leukoencephalopathy
• Fatigue

Cardiovascular Disorders

• Tachycardia
• Bradycardia
• Palpitations
• Atrial fibrillation
• Myocardial ischaemia
• Myocardial infarction
• Flushing
• Hypotension
• Hypertension
• Pericarditis
• Pericardial effusion
• Cardiac disorders (non-MS patients previously treated with potentially cardiotoxic agents)
  - Congestive heart failure
  - Cardiomyopathy
  - Decreased ejection fraction

Respiratory Disorders

• Dyspnoea
• Cough
• Epistaxis
• Hiccups
• Oropharyngeal pain
• Lower respiratory tract infection
• Upper respiratory tract infection
• Throat tightness
• Throat irritation
• Asthma
• Pulmonary alveolar haemorrhage
• Influenza
• Pneumonia
• Pneumonitis
• Acute sinusitis
• Tuberculosis
• Nasopharyngitis
• Bronchitis

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea
• Dyspepsia
• Stomatitis
• Constipation
• Gastro-oesophageal reflux disease
• Gingival bleeding
• Dry mouth
• Dysphagia
• Gastroenteritis
• Haematochezia
• Oral candidiasis
• Tooth infection
• Gingivitis
• Tonsilitis
• Oral herpes
• Appendicitis

Hepatobiliary Disorders

• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Cholecystitis
  - Acalculous cholecystitis, including acute acalculous cholecystitis
• Autoimmune hepatitis
• Hepatitis (associated with EBV infection)

Genitourinary Disorders

• Proteinuria
• Haematuria
• Nephrolithiasis
• Nephropathies
  - Anti-glomerular basement membrane disease
• Ketonuria
• Menorrhagia
• Vulvovaginal candidiasis
• Irregular menstruation
• Cervical dysplasia
• Amenorrhoea
• Urinary tract infection
• Vaginal infection
• Anogenital warts

Endocrine and Metabolic Disorders

• Basedow's disease
• Thyroid disorders
• Hyperthyroidism
• Hypothyroidism
• Autoimmune thyroiditis
  - Subacute thyroiditis
• Goitre
• Anti-thyroid antibody positive
• Decreased appetite
• Decreased weight
• Increased weight
• Increased blood glucose

Musculoskeletal Disorders

• Myalgia
• Muscle weakness
• Arthralgia
• Back pain
• Pain in extremity
• Muscle spasms
• Neck pain
• Musculoskeletal pain
• Musculoskeletal stiffness
• Limb discomfort

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Pruritus
• Generalised rash
• Erythema
• Ecchymosis
• Alopecia
• Hyperhidrosis
• Acne
• Blister
• Night sweats
• Skin lesion
• Swelling face
• Eczema
• Dermatitis
• Skin papilloma
• Infusion site pain
• Onychomycosis
• Fungal infection
• Cellulitis
• Infusion site pain
• Contusion

Immune, Blood and Lymphatic System Disorders

• Lymphopenia
• Leukopenia
• Neutropenia
• Lymphadenopathy
• Immune thrombocytopenic purpura
  - Easy bruising
  - Petechiae
  - Spontaneous mucocutaneous bleeding (e.g. epistaxis, haemoptysis)
  - Heavier than normal or irregular menstrual bleeding
• Thrombocytopenia
• Anaemia
• Decreased haematocrit
• Leukocytosis
• Pancytopenia
• Haemolytic anaemia
• Acquired haemophilia A
• Haemophagocytic lymphistiocytosis
• Herpes virus infection
  - Herpes simplex
  - Genital herpes
  - Herpes virus infection
  - Genital herpes simplex
  - Herpes dermatitis
  - Ophthalmic herpes simplex
  - Positive herpes simplex serology
• Herpes zoster infection
  - Cutaneous disseminated herpes zoster
  - Ophthalmic herpes zoster
  - Ophthalmic herpes
  - Neurological herpes zoster infection
  - Meningitis herpes zoster
• Listeriosis/listeria meningitis
• Cytokine release syndrome
• Hypersensitivity
  - Including anaphylaxis
• Increased blood creatinine
• Decreased red blood cell count
• Positive bacterial test
• Increased mean cell volume
• Cytomegalovirus infection
• Epstein-Barr virus infection (including reactivation)
• Peripheral oedema
• Influenza-like illness
• Autoimmune events
  - Autoimmune haemolytic anaemia (non-MS patients)
  - Autoimmune thrombocytopenia (non-MS patients)
  - Aplastic anaemia (non-MS patients)
  - Guillain-Barré syndrome (non-MS patients)
  - Chronic inflammatory demyelinating polyradiculoneuropathy (non-MS patients)
• Infusion related reaction
  - Headache
  - Rash
  - Pyrexia
  - Nausea
  - Urticaria
  - Pruritus
  - Insomnia
  - Chills
  - Flushing
  - Fatigue
  - Dyspnoea
  - Dysgeusia
  - Chest discomfort
  - Generalised rash
  - Tachycardia
  - Bradycardia
  - Dyspepsia
  - Dizziness
  - Pain
  - Hypotension
  - Atrial fibrillation
  - Bronchospasm (non-MS patients)
  - Hypoxia (non-MS patients)
  - Syncope (non-MS patients)
  - Pulmonary infiltrates (non-MS patients)
  - Acute respiratory distress syndrome (non-MS patients)
  - Respiratory arrest (non-MS patients)
  - Myocardial infarction (non-MS patients)
  - Arrhythmias (non-MS patients)
  - Aute cardiac insufficiency (non-MS patients)
  - Cardiac arrest (non-MS patients)
• Fatal viral, bacterial, protozoan, and fungal infections (non-MS patients)
• Severe bleeding reactions (non-MS patients)
• Fever

Sensory Disorders

• Conjunctivitis
• Endocrine ophthalmopathy
• Blurred vision
• Diplopia
• Vertigo
• Ear pain
• Ear infection

Others

• Chills
• Chest discomfort
• Pain

• Beta interferon
• Glatiramer acetate
• Vaccines (inactivated)
• Vaccines (live)

• Full blood count with differential
  - CD4+ lymphocyte counts
• Platelets
• Cytomegalovirus antigen
• Thyroid function
• Urinalysis
• Renal function
• Vital signs
• Blood pressure
• Hepatitis B virus (HBV) screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen
• Serum creatinine
• Hepatic function
  - Serum transaminases
  - Total bilirubin
• Cardiac function
  - Electrocardiogram
• Skin exam

Specific cases may require

• Coagulopathy panel
  -  Activated partial thromboplastin time (aPTT)
• Human papillomavirus screening
• Latent infection screening 

Additional observations

• Infusion reactions (See Additional Prescribing Points)
• Signs and symptoms of
  - Infections
  - Progressive multifocal leukoencephalopathy
  - Haemophagocytic lymphohistiocytosis
  - Thrombotic thrombocytopenic purpura
• Onset of autoimmune disorders

Pre-treatment

• Patients should be pre-treated with corticosteroids immediately prior to alemtuzumab administration on each of the first 3 days of any treatment course
• In clinical trials, patients were pre-treated with 1000mg methylprednisolone for the first 3 days of each alemtuzumab treatment course
• Pretreatment with antihistamines and/or antipyretics prior to alemtuzumab administration may also be considered
• Oral prophylaxis for herpes infection should be administered to all patients starting on the first day of each treatment course and continuing for a minimum of 1 month following treatment with alemtuzumab
•  In clinical trials, patients were administered aciclovir 200mg twice a day or equivalent

Follow-up of patients

• The therapy is recommended as an initial treatment of 2 courses with up to 2 additional treatment courses if needed, with safety follow-up of patients from initiation of the first treatment course and for at least 48 months after the last infusion of the second treatment course
• If an additional third or fourth course is administered, continue safety follow-up for at least 48 months after the last infusion

Infusion instructions to reduce serious reactions temporally associated with alemtuzumab infusion

• Pre-infusion evaluations:
  • Obtain a baseline ECG and vital signs, including heart rate and blood pressure measurement
  • Perform laboratory tests (complete blood count with differential, serum transaminases, serum creatinine, test of thyroid function and urinanalysis with microscopy
• During infusions:
  • Perform continuous/ frequent (at least every hour) monitoring of heart rate, blood pressure and overall clinical status of the patients
  • Discontinue the infusion
    - In case of a severe adverse event
    - If the patient shows clinical symptoms suggesting development of a serious adverse event associated with the infusion (myocardial ischemia, hemorrhagic stroke, cervico-cephalic arterial dissection or pulmonary alveolar haemorrhage
• Post infusion:
  • Observation for infusion reactions is recommended for a minimum of 2 hours after alemtuzumab infusion
  • Patients with clinical symptoms suggesting development of a serious adverse event temporarily associated with the infusion (myocardial ischemia, haemorrhagic stroke, cervico-cephalic arterial dissection or pulmonary alveolar haemorrhage) should be closely monitored until complete resolution of the symptoms
  • The observation time should be extended (hospitalisation) as appropriate. The patients should be educated on the potential for delayed onset of infusion associated reactions and instructed to report symptoms and seek appropriate medical care
  • Platelet count should be obtained immediately after infusion on days 3 and 5 of the first infusion course, as well as immediately after infusion on day 3 of any subsequent course
  • Clinically significant thrombocytopenia needs to be followed until resolution. Referral to a haematologist for management should be considered

Recommended laboratory tests for monitoring patients

• Clinical examination and laboratory tests should be conducted at periodic intervals until at least 48 months following the last treatment course of alemtuzumab in order to monitor for early signs of autoimmune diseases:
  • Complete blood count with differential, serum transaminases and serum creatinine levels (prior to treatment initiation and at monthly intervals thereafter)
  • Urinalysis with microscopy (prior to treatment initiation and at monthly intervals thereafter)
  • A test of thyroid function, such as thyroid stimulating hormone level (prior to treatment initiation and every 3 months thereafter)

Alemtuzumab, is a recombinant DNA-derived humanised monoclonal antibody directed against the 21-28 kD cell surface glycoprotein CD52. Alemtuzumab is an IgG1 kappa antibody with human variable framework and constant regions, and complementary-determining regions from a murine (rat) monoclonal antibody. The antibody has an approximate molecular weight of 150 kD.

Alemtuzumab binds to CD52, a cell surface antigen present at high levels on T (CD3⁺) and B (CD19⁺) lymphocytes, and at lower levels on natural killer cells, monocytes, and macrophages. There is little or no CD52 detected on neutrophils, plasma cells, or bone marrow stem cells. Alemtuzumab acts through antibody-dependent cellular cytolysis and complement-mediated lysis following cell surface binding to T and B lymphocytes.

The mechanism by which alemtuzumab exerts its therapeutic effects in MS is not fully elucidated. However, research suggests immunomodulatory effects through the depletion and repopulation of lymphocytes, including:
- Alterations in the number, proportions, and properties of some lymphocyte subsets post-treatment
- Increased representation of regulatory T cell subsets
- Increased representation of memory T- and B-lymphocytes
- Transient effects on components of innate immunity (i.e., neutrophils, macrophages, NK cells)

The reduction in the level of circulating B and T cells by alemtuzumab and subsequent repopulation may reduce the potential for relapse, which ultimately delays disease progression.

Injection (per 1ml) 10mg

• Mabcampath (Genzyme Biopharma) originator
• Lemtrada (Sanofi) originator

Injection (per 1ml) 30mg

• Mabcampath (Genzyme Biopharma) originator (Discontinued - 4/07/2018)