Chemical formula: C₆₄₆₈H₁₀₀₆₆N₁₇₃₂O₂₀₀₅S₄₀ Molecular mass: 145,453.8 g/mol
Alemtuzumab interacts in the following cases:
The safety of immunisation with live viral vaccines following a course of alemtuzumab treatment has not been formally studied in controlled clinical trials in MS and should not be administered to MS patients who have recently received a course of alemtuzumab.
In a controlled clinical trial in MS patients recently treated with beta interferon and glatiramer acetate were required to discontinue treatment 28 days before initiating treatment with alemtuzumab.
As for any immune modulating medicinal product, before initiating a course of alemtuzumab treatment, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to treatment initiation with alemtuzumab. To allow for the full effect of the VZV vaccination to occur, treatment with alemtuzumab should be postponed for 6 weeks following vaccination.
As with other immunomodulatory therapies, caution should be exercised in initiating alemtuzumab therapy in patients with pre-existing and/or an on-going malignancy. It is not currently known if alemtuzumab confers a higher risk for developing thyroid malignancies, since thyroid autoimmunity may itself be a risk factor for thyroid malignancies.
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 IgG 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.
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 suckling newborn/infant cannot be excluded. Therefore, breast-feeding 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 breast-milk may outweigh the risks of potential exposure to alemtuzumab for the suckling newborn/infant.
There have been no studies to assess the carcinogenic or mutagenic potential of alemtuzumab.
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 12 mg or 24 mg), 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.
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.
Alemtuzumab has minor influence on the ability to drive and use machines. Most patients experience IARs which occur during or within 24 hours after treatment with alemtuzumab. Some of the IARs (e.g. dizziness) could temporarily impact the patient’s ability to drive or use machines and caution should be exercised until these are resolved.
A total of 1,486 patients treated with alemtuzumab (12 mg or 24 mg) constituted the safety population in a pooled analysis of MS clinical studies with a median follow-up of 6.1 years (maximum 12 years), resulting in 8,635 patient-years of safety follow-up.
The most important adverse reactions are autoimmunity (ITP, thyroid disorders, nephropathies, cytopenias), IARs, and infections. These are described in section 4.4.
The most common adverse reactions with alemtuzumab (in ≥20% of patients) were rash, headache, pyrexia, and respiratory tract infections.
The list below is based on the pooled safety data on all alemtuzumab 12 mg-treated patients during all available follow up in clinical trials. Adverse reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). Frequencies are defined according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions have been presented in order of decreasing seriousness.
Adverse reactions in study 1, 2, 3 and 4 observed in alemtuzumab 12 mg treated patients and post-marketing surveillance:
Very Common: Upper respiratory tract infection, urinary tract infection, herpes virus infection1
Common: Herpes zoster infections2, lower respiratory tract infections, gastroenteritis, oral candidiasis, vulvovaginal candidiasis, influenza, ear infection, pneumonia, vaginal infection, tooth infection
Uncommon: Onychomycosis, gingivitis, fungal skin infection, tonsillitis, acute sinusitis, cellulitis, pneumonitis, tuberculosis, cytomegalovirus infection
Not known: Listeriosis/listeri a meningitis, Epstein-Barr virus (EBV) reactivation
Common: Skin papilloma
Very Common: Lymphopenia, leukopenia, including neutropenia
Common: Lymphadenopathy, immune thrombocytopenic purpura, thrombocytopenia, anaemia haematocrit decreased, leukocytosis
Uncommon: Pancytopenia, haemolytic anaemia, acquired haemophilia A
Rare: Haemophagocytic lymphohistiocytos is (HLH)
Common: Cytokine release syndrome*, hypersensitivity including anaphylaxis*
Very Common: Basedow’s disease, hyperthyrodisim, hypothyroidism
Common: Autoimmune thyroiditis including thyroiditis subacute, goitre, anti-thyroid antibody positive
Uncommon: Decreased appetite
Common: Insomnia*, anxiety, depression
Very Common: Headache*
Common: MS relapse, dizziness*, hypoaesthesia, paraesthesia, tremor, dysgeusia*, migraine*
Uncommon: Sensory disturbance, hyperaesthesia, tension headache
Not known: Haemorrhagic stroke**, cervicocephalic arterial dissection**
Common: Conjunctivitis, endocrine ophthalmopathy, vision blurred
Uncommon: Diplopia
Common: Vertigo
Uncommon: Ear pain
Very Common: Tachycardia*
Common: Bradycardia*, palpitations*
Uncommon: Atrial fibrillation*
Not known: Myocardial ischaemia**, myocardial infarction**
Very Common: Flushing*
Common: Hypotension*, hypertension*
Common: Dyspnoea*, cough, epistaxis, hiccups, oropharyngeal pain, asthma
Uncommon: Throat tightness*, throat irritation
Not known: Pulmonary alveolar haemorrhage**
Very Common: Nausea*
Common: Abdominal pain, vomiting, diarrhoea dyspepsia*, stomatitis
Uncommon: Constipation, gastro-oesophageal reflux disease, gingival bleeding, dry mouth, dysphagia, gastrointestinal disorder, haematochezia
Common: Aspartate aminotransferase increased, alanine aminotransferase increase
Uncommon: Cholecystitis including acalculous cholecystitis and acute acalculous cholecystitis
Not known: Autoimmune hepatitis
Very Common: Urticaria*, rash*, pruritus*, generalised rash*
Common: Erythema*, ecchymosis, alopecia, hyperhidrosis, acne, skin lesion, dermatitis
Uncommon: Blister, night sweats, swelling face, eczema
Common: Myalgia, muscle weakness, arthralgia, back pain, pain in extremity, muscle spasms, neck pain, musculoskeletal pain
Uncommon: Musculoskeletal stiffness, limb discomfort
Common: Proteinuria, haematuria
Uncommon: Nephrolithiasis, ketonuria, nephropathies including anti-GBM disease
Common: Menorrhagia, menstruation irregular
Uncommon: Cervical dysplasia, amenorrhoea
Very Common: Pyrexia*, fatigue*, chills*
Common: Chest discomfort*, pain*, oedema peripheral, asthenia, influenza-like illness, malaise, infusion site pain
Common: Blood creatinine increased
Uncommon: Weight decreased, weight increased, red blood cell count decreased, bacterial test positive, blood glucose increased, mean cell volume increase
Common: Contusion, infusion related reaction
1 Herpes virus infections include PTs: Oral herpes, Herpes simplex, Genital herpes, Herpes virus infection, Genital herpes simplex, Herpes dermatitis, Ophthalmic herpes simplex, Herpes simplex serology positive.
2 Herpes zoster infections include PTs: Herpes zoster, Herpes zoster cutaneous disseminated, Ophthalmic herpes zoster, Herpes ophthalmic, Herpes zoster infection neurological, Herpes zoster meningitis.
Terms marked with asterisk (*) include adverse reactions reported as Infusion Associated Reactions.
Terms marked with two asterisks (**) include adverse reactions observed in the post marketing setting which have occurred in the majority of cases with time to onset within 1-3 days of alemtuzumab infusion, following any of the doses during the treatment course.
Cases of severe (including fatal) neutropenia have been reported within 2 months of alemtuzumab infusion.
The type of adverse reactions including seriousness and severity observed in alemtuzumab treatment groups through all available follow-up including patients who received additional treatment courses were similar to those in the active-controlled studies. The incidence of IARs was higher in course 1 than in subsequent courses.
In patients continuing from controlled clinical studies and who did not receive any additional alemtuzumab after the initial 2 treatment courses, the rate (events per person-year) of most adverse reactions was comparable to or reduced in years 3-6 as compared to years 1 and 2. The rate of thyroid adverse reactions was highest in year three and declined thereafter.
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