ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT
MabCampath 10 mg/ml concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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One ml contains 10 mg of alemtuzumab.
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authorised
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Each ampoule contains 30 mg of alemtuzumab.
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Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for 21-28 kD lymphocyte cell surface glycoprotein (CD52). The antibody is produced in mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
4. CLINICAL PARTICULARS
4. 1 Therapeutic indications
MabCampath is indicated for the treatment of patients with B -cell chronic lymphocytic leukaemia (B-CLL) for whom fludarabine combination chem therapy is not appropriate.
4.2 Posologyproductandmethodofadminisraion
MabCampath should be administered under he supervision of a physician experienced in the use of cancer therapy.
Posology
During the first week f eatment, MabCampath should be administered in escalating doses: 3 mg on day 1, 10 mg on day 2 and 30 mg on day 3 assuming that each dose is well tolerated. Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days up to a maximum of 12 weeks.
MedicinalInmostptients,dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute moder te to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills,
rashes a d bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated before further dose escalation is attempted (see section 4.4).
Median duration of treatment was 11.7 weeks for first-line patients and 9.0 weeks for previously treated patients.
Once patient meets all laboratory and clinical criteria for a complete response, MabCampath should be discontinued and the patient monitored. If a patient improves (i.e. achieves a partial response or stable disease) and then reaches a plateau without further improvement for 4 weeks or more, then MabCampath should be discontinued and the patient monitored. Therapy should be discontinued if there is evidence of disease progression.
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Concomitant medicinal products
Premedications
Patients should be premedicated with oral or intravenous steroids, an appropriate antihistamine and analgesic 30-60 minutes prior to each MabCampath infusion during dose escalation and as clinically indicated thereafter (see section 4.4).
Prophylactic antibiotics
Antibiotics and antivirals should be administered routinely to all patients throughout and foll wing treatment (see section 4.4).
Dose modification guidelines
There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.
permanently discontinued if autoimmune anaemia or autoimmulongerthrombocytopenia appears. The following table outlines the recommended procedure for d se m dification following the occurrence of haematological toxicity while on therapy:
In the event of serious infection or severe haematological toxicity MabCampath should be interrupted until the event resolves. It is recommended that MabCampath should be int upted in patients whose
platelet count falls to < 25,000/ml or whose absolute neutrophil count (ANC) drops to < 250/ml. MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be
3
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Haematologic values
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Dose modification*
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ANC < 250/μl and/or platelet count ≤25,000/μl
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For first occurrence
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Withhold MabCampath therapy. Resume
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MabCampath at 30 mg when ANC ≥ 500/μl and
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platelet count ≥ 50,000/μl.
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For second occurrence
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Withhold MabCampath therapy. Resume
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MabCampath at 10 mg when ANC ≥ 500/μl and
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platelet count ≥ 50,000/μl.
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For third occurrence
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Discontinue MabCampath therapy.
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≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μl and/
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baseline platelet count ≤ 25,000/μl
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For first occurrence
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Withhold MabCampath therapy. Res me
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MabCampath at 30 mg upon ret rn to baseline
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value(s).
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For second occurrence
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Withhold MabCampath the apy. Resume
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authorised
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MabCampath at 10 mg upon return to baseline
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value(s).
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For third occurrence
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Discontinue MabCampath therapy.
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*If the delay between dosing is ³ 7 days, initiate therapy at MabCampath 3 mg and escalate to 10 mg
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and then to 30 mg as tolerated
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Special populations
Elderly (over 65 years of age)
The safety and efficacyproductofMabCampathin children aged less than 17 years of age have not been established. No ta are available.
Recommendations are as stated above for adults. Patients should be monitored carefully (see section 4.4).
Patients with renal or hepatic impairment
No studies have been nducted.
Paediatric population
Method of administration
The MabCampath solution must be prepared according to the instructions provided in section 6.6. All oses should be administered by intravenous infusion over approximately 2 hours.
Medicinal4.3Contraindications
- Hypersensitivity to alemtuzumab, to murine proteins or to any of the excipients.
- Active systemic infections.
- HIV.
- Active second malignancies.
- Pregnancy.
4
4.4 Special warnings and precautions for use
Acute adverse reactions, which may occur during initial dose escalation and some of which may be due to the release of cytokines, include hypotension, chills/rigors, fever, shortness of breath and rashes. Additional reactions include nausea, urticaria, vomiting, fatigue, dyspnoea, headache, pruritus, diarrhoea and bronchospasm. The frequency of infusion reactions was highest in the first week of therapy, and declined in the second or third week of treatment, in patients treated with MabCampath both as first line therapy and in previously treated patients.
If these events are moderate to severe, then dosing should continue at the same level prior to each do e escalation, with appropriate premedication, until each dose is well tolerated. If therapy is withheld for more than 7 days, MabCampath should be reinstituted with gradual dose escalation.
Transient hypotension has occurred in patients receiving MabCampath. Caution should be used in treating patients with ischaemic heart disease, angina and/or in patients receivingauthorisedananiyperensivemedicinalproduct.MyocardialinfarctionandcardiacarresthavebeenobservedinassociaionwithMabCampathinfusioninthispatientpopulation.Assessmentandongoingmonitoringofcardiacfunction(e..echocardiogaphy,hertteandbodyweight)shouldbeconsideredinpatientspreviouslytreatedwithpotentiallycadiotoxicagents.
It is recommended that patients be premedicated with orallongerorintravenousstroids 30 - 60 minutes prior to each MabCampath infusion during dose escalati and as clinically indicated. Steroids may
be discontinued as appropriate, once dose escalation has been achieved. In addition, an oral antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, e.g. paracetamol 500 mg, may be given. In the event that acute infusion reactions persist, the infusi n time may be extended up to 8 hours from the time of reconstitution of MabCampath in solution f r infusi n.
Profound lymphocyte depletion, an expected pharmac l gical effect of MabCampath, inevitably occurs and may be prolonged. CD4 and CD8 T -cell c unts begin to rise from weeks 8-12 during
treatment and continue to recover for several mo ths following the discontinuation of treatment. In patients receivingproductMabCampathasfirstlineherapy, the recovery of CD4+ counts to ≥200 cells/µl occurred by 6 months post-treatment, however, at 2 months post-treatment the median was 183
cells/ml. In previously treated patients re eiving MabCampath, the median time to reach a level of 200 cells/ml is 2 months following last inf sion with MabCampath but may take more than 12 months to approximate pretreatment levels. This may predispose patients to opportunistic infections. It is highly recommended that anti-infective prophylaxis (e.g. trimethoprim/sulfamethoxazole 1 tablet twice daily, 3 times weekly, or other phylaxis againstPneumocystis jiroveci pneumonia (PCP) and an effective
oral anti- herpes agent, such as famciclovir, 250 mg twice daily) should be initiated while on therapy and for a minimum of 2 months following completion of treatment with MabCampath or until the
CD4+ count has recovered to 200 cells/ml or greater, whichever is the later. MedicinalThepotetilforn increased risk of infection-related complications may exist following treatment
w th multiple chemotherapeutic or biological agents.
Be ause of the potential for Transfusion Associated Graft Versus Host Disease (TAGVHD) it is re ommended that patients who have been treated with MabCampath receive irradiated blood products.
Asymptomatic laboratory positive Cytomegalovirus (CMV) viraemia should not necessarily be considered serious infection requiring interruption of therapy. Ongoing clinical assessment should be performed for symptomatic CMV infection during MabCampath treatment and for at least 2 months following completion of treatment.
Transient grade 3 or 4 neutropenia occurs very commonly by weeks 5-8 following initiation of treatment. Transient grade 3 or 4 thrombocytopenia occurs very commonly during the first 2 weeks of therapy and then begins to improve in most patients. Therefore, haematological monitoring of patients
5
is indicated. If a severe haematological toxicity develops, MabCampath treatment should be interrupted until the event resolves. Treatment may be reinstituted following resolution of the haematological toxicity (see section 4.2). MabCampath should be permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears.
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Complete blood counts and platelet counts should be obtained at regular intervals during MabCampath
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therapy and more frequently in patients who develop cytopenias.
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It is not proposed that regular and systematic monitoring of CD52 expression should be carried out as routine clinical practice. However, if retreatment is considered, it may be prudent to confirm the presence of CD52 expression. In data available from first line patients treated with MabCampath, lo of CD52 expression was not observed around the time of disease progression or death.
Patients may have allergic or hypersensitivity reactions to MabCampath and to murine c imeric monoclonal antibodies.
Medicinal products for the treatment of hypersensitivity reactions, as well as preparedness to institute emergency measures in the event of reaction during administration is necessary (see section 4.2).
Males and females of childbearing potential should use effective contraceptive measures during longertreatmentandfor6monthsfollowingMabCampaththerapy(seesections4.6and 5.3).NostudieshavebeenconductedwhichspecificallyaddresstheeffectofaMabCampath
disposition and toxicity. In general, older patients (over 65 years of a e) tolerate cytotoxic therapy less well than younger individuals. Since CLL occurs comm nly in this older age group, these patients should be monitored carefully (see section 4.2). In the studies in first line and previously treated patients no substantial differences in safety and efficacy re ated to age were observed; however the sizes of the databases are limited.
4.5 Interaction with other medicinal products a d ther forms of interaction
Although no formal drug interaction studies have been performed with MabCampath, there are no known clinically significant intera tions of MabCampath with other medicinal products. Because MabCampath is a recombinant h manized protein, a P450 mediated drug-drug interaction would not be expected. However, it is recommended that MabCampath should not be given within 3 weeks of other chemotherapeutic agents.
Although it has not been studied, it is recommended that patients should not receive live viral vaccines in, at least, the 12 months following MabCampath therapy. The ability to generate a primary or anamnestic humoral res onse to any vaccine has not been studied.
4.6 Ferti ity, pregnancy and lactation
MedicinaPregcyl
MabCampath is contraindicated during pregnancy. Human IgG is known to cross the placental barrier; MabCampath may cross the placental barrier as well and thus potentially cause foetal B and T cell lymphocyte depletion. Animal reproduction studies have not been conducted with MabCampath. It is not known if MabCampath can cause foetal harm when administered to a pregnant woman.
Males and females of childbearing capacity should use effective contraceptive measures during treatment and for 6 months following MabCampath therapy (see section 5.3).
Lactation
It is not known whether MabCampath is excreted in human milk. If treatment is needed, breast-feeding should be discontinued during treatment and for at least 4 weeks following MabCampath therapy.
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4.8 Undesirable effects
4.7 Effects on ability to drive and use machines
Fertility
There are no definitive studies of MabCampath which assess its impact on fertility. It is not known if MabCampath can affect human reproductive capacity (see section 5.3).
No studies on the effects on the ability to drive and use machines have beenauthorisedperformed.However, caution should be exercised as confusion and somnolence have been reported.
The tables below report adverse reactions by MedDRA system organ classes (MedDRA SOCs). T e frequencies are based on clinical trial data.
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
The frequencies are defined as: 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). No information available for events that occur at lower frequency, due to the size of the population studied; n=147 for first line treated patients and n=149 for previously treated patients.
The most frequent adverse reactions with MabCampath are: i fusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspn ea), cyt pe ias (neutropenia, lymphopenia, thrombocytopenia, anaemia), infections (CMV viraemia, CMV infection, other infections), gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most frequent serious adverse reacti ns are cytopenias, infusion reactions, and immunosuppression/infections.
Undesirable effects in first line patients
Safety data in first-line B-CLL patients are based on adverse reactions that occurred on study in 147 patients enrolled in a randomized, ontrolled study of MabCampath as a single agent administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks, inclusive of dose escalation period. Approximately 97% of first-line patients experienced adverse reactions; the most commonly reported reactions in first line patients usually occurred in the first week of therapy.
Within each frequency g ouping, undesirable effects observed during treatment or within 30 days following the com letion of treatment with MabCampath are presented in order of decreasing seriousness.
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System organ class
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Very common
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Common
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Uncommon
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Infections and
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Cytomegalovirus
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Pneumonia
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Sepsis
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infestations
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viraemia
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Bronchitis
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Staphylococcal
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Cytomegalovirus
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Pharyngitis
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bacteraemia
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infection
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Oral candidiasis
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Tuberculosis
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Bronchopneumonia
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Herpes ophthalmicus
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Beta haemolytic
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streptococcal infection
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Candidiasis
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Genital candidiasis
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Urinary tract infecti n
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Cystitis
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Body tinea
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N soph ryngitis
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Rhinitis
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Blood and lymphatic
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Febrile neutropenia
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Ag anulocytosis
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system disorder
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Neutropenia
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Lymphopenia
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Leukopenia
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Lymphadenopathy
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Thrombocytopenia
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Epistaxis
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Anaemia
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Immune system
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Anaphylactic reaction
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disorders
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Hypersensitivity
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Metabolism and
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Weight decreased
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Tumour lysis syndrome
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nutrition disorders
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Hyperglycaemia
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Protein total decreased
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Anorexia
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Psychiatric disorders
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Anxiety
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Nervous system
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Syncope
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Vertigo
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disorders
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Dizziness
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Tremor
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Paraesthesia
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Hypoesthesia
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Headache
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Eye disorders
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Conjunctivitis
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Cardiac disorders
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Cyanosis
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Cardiac arrest
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Bradycardia
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Myocardial infarction
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Tachycardia
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Angina pectoris
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Sinus tachycardia
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Atrial fibrillation
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Arrhythmia
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supraventricular
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Sinus bradycardia
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Supraventricular
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extrasystoles
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Vascular disorders
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Hypotension
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Hypertension
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Orthostatic hypotension
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Hot flush
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Flushing
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Respiratory, thoracic
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Bronchospasm
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Hypoxia
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and mediastinal
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Dyspnoea
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Pleural effusion
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disorders
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Dysphonia
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Rhinorrhoea
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System organ class
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Very common
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Common
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Uncommon
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Gastrointestinal
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Nausea
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Vomiting
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Ileus
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disorders
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Abdominal pain
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Oral discomfort
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Stomach discomfort
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Diarrhoea
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authorised
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Skin and subcutaneous
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Urticaria
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Dermatitis allergic
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Rash pruritic
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tissue disorders
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Rash
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Pruritus
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Rash macular
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Hyperhidrosis
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Rash erythematous
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Erythema
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Dermatitis
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Musculoskeletal and
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Myalgia
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Bone pain
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connective tissue
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Musculoskeletal
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Arthralgia
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disorders
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pain
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Musculoskeletal c est
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Back pain
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pain
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Muscle spasms
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Renal and urinary
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Urine tp decreased
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disorders
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Dys ria
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General disorders and
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Fever
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Fatigue
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Mucos l inflammation
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administration site
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Chills
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Asthenia
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Infusion site erythema
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conditions
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Localised oedema
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Infusion site oedema
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Malaise
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Acute infusion reactions including fever, chills, nausea, v miti g, hypotension, fatigue, rash, urticaria, dyspnoea, headache, pruritus and diarrhoea have been rep rted. The majority of these reactions are mild to moderate in severity. Acute infusion reactions usua y occur during the first week of therapy and substantially decline thereafter. Grade 3 or 4 infusi n reactions are uncommon after the first week of therapy.
Undesirable effects in previously treated pa ie s
Safety data in previously treated B-CLL patients are based on 149 patients enrolled in single-arm studies of MabCampath (Studies 1, 2, and 3). More than 80% of previously treated patients may be expected to experience adverse reactions; the most commonly reported reactions usually occur during the first week of therapy.
Within each frequency g uping, undesirable effects are presented in order of decreasing seriousness.
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System organ class
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Very common
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Common
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Uncommon
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Infections and
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Sepsis
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Cytomegalovirus
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Bacterial infection
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infestations
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Pneumonia
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infection
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Viral infection
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Herpes simplex
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Pneumocystis jiroveci
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Fungal dermatitis
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infection
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Laryngitis
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Pneumonitis
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Rhinitis
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Fungal infection
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Onychomycosis
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Candidiasis
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Herpes zoster
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Abscess
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Urinary tract infection
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Sinusitis
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Bronchitis
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Upper respiratory tract
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infection
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Pharyngitis
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Infection
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Neoplasms, benign,
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Lymphoma – like
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malignant and
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disorder
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unspecified (incl. cysts
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and polyps)
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Blood and lymphatic
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Granulocytopenia
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Febrile
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eutrope ia
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Aplasia bone marrow
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system disorder
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Thrombocytopenia
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Pancytope ia
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Disseminated
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Anaemia
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Leuk pe
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ia
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intravascular
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Lymph penia
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coagulation
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Purpura
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Haemolytic anaemia,
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Decreased haptoglobin
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Bone marrow
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depression
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Epistaxis
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Gingival bleeding
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Haematology test
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abnormal
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Immune system
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Allergic reaction
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disorders
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Severe anaphylactic
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and other
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hypersensitivity
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reactions
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Metabolism nd
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Anorexia
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Hyponatraemia
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Hypokalaemia
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nutrition disorders
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Hypocalcaemia
|
Diabetes mellitus
|
|
|
|
|
Weight decrease
|
aggravated
|
|
|
|
|
Dehydration
|
|
|
|
|
|
Thirst
|
|
|
|
|
|
|
|
|
|
|
Psychiatric disorders
|
|
Confusion
|
Depersonalisation
|
|
|
|
|
Anxiety
|
|
Personality disorder
|
|
|
|
|
Depression
|
Abnormal thinking
|
|
|
|
|
Somnolence
|
Impotence
|
|
|
|
|
Insomnia
|
Nervousness
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
10
|
|
Nervous system
|
Headache
|
|
Vertigo
|
Syncope
|
|
|
disorders
|
|
|
Dizziness
|
Abnormal gait
|
|
|
|
|
|
Tremor
|
Dystonia
|
|
|
|
|
|
Paresthesia
|
Hyperesthesia
|
|
|
|
|
|
Hypoesthesia
|
Neuropathy
|
|
|
|
|
|
Hyperkinesia
|
Taste perversion
|
|
|
|
|
|
Taste loss
|
|
|
|
|
|
|
|
|
|
|
Eye disorders
|
|
|
Conjunctivitis
|
Endophthalmitis
|
|
|
Ear and labyrinth
|
|
|
|
Deafness
|
|
|
disorders
|
|
|
|
Tinnitus
|
|
|
|
|
|
|
|
|
|
Cardiac disorders
|
|
|
Palpitation
|
Cardiac arrest
|
|
|
|
|
|
Tachycardia
|
Myocardial infarcti n
|
|
|
|
|
|
|
Atrial fibrillati n
|
|
|
|
|
|
|
Supraven ricular
|
|
|
|
|
|
|
tachycardia
|
|
|
|
|
|
|
Arrhythmia
|
|
|
|
|
|
|
Br dyc rdia
|
|
|
|
|
|
|
Abnorm l ECG
|
|
|
|
|
|
|
|
|
|
Vascular disorders
|
Hypotension
|
|
Hypertension
|
Pe ipheral ischaemia
|
|
|
|
|
|
Vasospasm
|
|
|
|
|
|
|
Flushing
|
|
|
|
Respiratory, thoracic
|
Dyspnoea
|
|
Hypoxia
|
Stridor
|
|
|
and mediastinal
|
|
|
Haemoptysis
|
Throat tightness
|
|
|
disorders
|
|
|
Br nch spasm
|
Pulmonary infiltration
|
|
|
|
|
|
Coughing
|
Pleural effusion
|
|
|
|
|
|
|
Breath sounds
|
|
|
|
|
|
|
decreased
|
|
|
|
|
|
|
Respiratory disorder
|
|
|
|
|
|
|
|
|
|
Gastrointestinal
|
Vomiting
|
|
Gastrointestinal
|
Gastroenteritis
|
|
|
disorders
|
Nausea
|
|
haemorrhage
|
Tongue ulceration
|
|
|
|
Diarrhoea
|
|
Ulcerative stomatitis
|
Gingivitis
|
|
|
|
|
|
Stomatitis
|
Hiccup
|
|
|
|
|
|
Abdominal pain
|
Eructation
|
|
|
|
|
|
Dyspepsia
|
Dry mouth
|
|
|
|
|
|
Constipation
|
|
|
|
|
|
|
Flatulence
|
|
|
|
Hepatobiliary disorde s
|
|
|
Hepatic function
|
|
|
|
|
|
|
abnormal
|
|
|
|
Skin and subcutaneous
|
Pruritus
|
|
Bullous eruption
|
Maculo-papular rash
|
|
|
tissue disorders
|
Urticaria
|
|
Erythematous rash
|
Skin disorder
|
|
|
|
Rash
|
|
|
|
|
|
|
Hyperhidrosis
|
|
|
|
|
|
|
|
|
|
|
|
|
Mus uloskeletal and
|
|
|
Arthralgia
|
Leg pain
|
|
|
onne tive tissue
|
|
|
Myalgia
|
Hypertonia
|
|
|
sorders
|
|
|
Skeletal pain
|
|
|
|
|
|
|
Back pain
|
|
|
|
|
|
|
|
|
|
|
Renal and urinary
|
|
|
|
Haematuria
|
|
|
disorders
|
|
|
|
Urinary incontinence
|
|
|
|
|
|
|
Urine flow decreased
|
|
|
|
|
|
|
Polyuria
|
|
|
|
|
|
|
Renal function
|
|
|
|
|
|
|
abnormal
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
11
|
|
|
General disorders and
|
Chills
|
Chest pain
|
Pulmonary oedema
|
|
administration site
|
Fever
|
Influenza-like
|
Peripheral oedema
|
|
conditions
|
Fatigue
|
symptoms
|
Periorbital oedema
|
|
|
|
Mucositis
|
Mucosal ulceration
|
|
|
|
Oedema mouth
|
Infusion site bruising
|
|
|
|
Oedema
|
Infusion site dermatitis
|
|
|
|
Asthenia
|
Infusion site pain
|
|
|
|
Malaise
|
|
|
|
|
Temperature change
|
|
|
|
|
sensation
|
|
|
|
|
Infusion site reaction
|
|
|
|
|
Pain
|
|
been reported following MabCampath administration. Theselongersymptomscanbeamelioratedauthorisedavoided if premedication and dose escalation are utilised (see section 4.4).
Undesirable effects observed during post-marketing surveillance
Infusion reactions: Serious and sometimes fatal reactions, including bronchospasm, hypoxia, syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory rrest, myocardial infarction, arrhythmias, acute cardiac insufficiency and cardiac arrest have been observed. Severe anaphylactic and other hypersensitivity reactions, including anaphylactic shock nd ngioedema, have
Infections and infestations: Serious and sometimes fatal viral (e. . adenovirus, parainfluenza, hepatitis B, progressive multifocal leukoencephalopathy (PML)), bacterial (i cluding tuberculosis and atypical
mycobacterioses, nocardiosis), protozoan (e.g. toxoplasma dii), a d fungal (e.g. rhinocerebralmucormycosis)infections,includingthoseduetoreactivatinflatentinfectionshaveoccurred during
post-marketing surveillance. The recommended anti- infective prophylaxis treatment appears to be effective in reducing the risk of PCP and herpes infecti ns (see section 4.4).
EBV-associated lymphoproliferative disorders, in some cases fatal, have been reported.
Blood and lymphatic system disorders: Severe bleeding reactions have been reported.
Immune system disorders: Serio s and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, a toimmune thrombocytopenia, aplastic anaemia, Guillain Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy have been reported. A positive C mbs test has also been observed. Fatal Transfusion Associated Graft Versus Host Disease (TAGVHD) has also been reported.
Metabolism and nutritional disorders: Tumour lysis syndrome with fatal outcome has been reported.
MedicinalNervoussystemdisorders: Intracranial haemorrhage has occurred with fatal outcome, in patients with thrombocytopenia.
Card ac disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported patients previously treated with potentially cardiotoxic agents.
4.9 Overdose
Patients have received repeated unit doses of up to 240 mg of MabCampath. The frequency of grade 3 or 4 adverse events, such as fever, hypotension and anaemia, may be higher in these patients. There is no known specific antidote for MabCampath. Treatment consists of discontinuation of MabCampath and supportive therapy.
12
First line B-CLL patients
5. PHARMACOLOGICAL PROPERTIES
5. 1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC04. Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibodyauthorisedspecificfor
21-28 kD lymphocyte cell surface glycoprotein (CD52) expressed primarily on the surface of normal and malignant peripheral blood B and T cell lymphocytes. Alemtuzumab was generated by the insertion of six complementarity-determining regions from an IgG2a rat monoclonal antibody into a human IgG1 immunoglobulin molecule.
Alemtuzumab causes the lysis of lymphocytes by binding to CD52, a highly expressed, non-modulating antigen which is present on the surface of essentially all B and T cell lymphocytes as well as monocytes, thymocytes and macrophages. The antibody mediates the lysis of lymphocy es via complement fixation and antibody-dependent cell mediated cytotoxicity. The antigen has been found on a small percentage (< 5%) of granulocytes, but not on erythrocytes or platelets. Alemt z mab does not appear to damage haematopoietic stem cells or progenitor cells.
The safety and efficacy of MabCampath were evaluated longerinaPhase3,op-label, randomized comparative trial of first line (previously untreated) Rai stage I-IV B-CLL pati nts requiring therapy
(Study 4). MabCampath was shown to be superior to chlorambucil as measured by the primary endpoint progression free survival (PFS) (see Figure 1).
Figure 1: Progression free survival in first ine study (by treatment group)
The secondary objectives included complete response (CR) and overall response (CR or partial response) rates using the 1996 NCIWG criteria, the duration of response, time to alternative treatment and safety of the two treatment arms.
13
Summary of first-line patient population and outcomes
|
|
Independent review of response rate and duration
|
|
|
MabCampath
|
Chlorambucil
|
P value
|
|
|
n=149
|
n=148
|
|
|
Median Age (Years)
|
59
|
60
|
Not Applicable
|
|
Rai Stage III/IV Disease
|
33.6%
|
33.1%
|
Not Applicable
|
|
|
|
|
|
|
Overall Response Rate
|
83.2%
|
55.4%
|
<0.0001*
|
|
Complete Response
|
24.2%
|
2.0%
|
<0.0001*
|
|
MRD negative****
|
7.4%
|
0.0%
|
0.0008*
|
|
Partial Response
|
59.1%
|
53.4%
|
Not Applicable
|
|
Duration of Response**, CR or
|
N=124
|
N=82
|
Not Applicable
|
|
PR (Months)
|
16.2
|
12.7
|
|
|
K-M median (95% Confidence
|
(11.5, 23.0)
|
(10.2, 14.3)
|
|
|
Interval)
|
|
|
|
|
Time to Alternative Treatment
|
23.3
|
14.7
|
0.0001***
|
|
(Months)
|
(20.7, 31.0)
|
(12.6, 16.8)
|
|
|
K-M median (95% Confidence
|
|
|
|
|
Interval)
|
|
|
|
*Pearson chi-square test or Exact test
* Duration of best response
* log-rank test stratified by Rai group (Stage I-II vs III-IV)
* by 4-colour flow
Cytogenetic analyses in first line B-CLL patie ts:
The cytogenetic profileproductofB-CLLhasbeeni creasi gly recognized as providing important prognosticinformationandmaypredictresponseeraintherapies.Ofthefirst-linepatients(n=282)inwhom
baseline cytogenetic (FISH) data were available in Study 4, chromosomal aberrations were detected in 82%, while normal karyotype was dete ted in 18%. Chromosomal aberrations were categorized according to Döhner’s hierarchical model. In first line patients, treated with either MabCampath or chlorambucil, there were 21 patients with the 17p deletion, 54 patients with 11q deletion, 34 patients with trisomy 12, 51 patients with normal karyotype and 67 patients with sole 13q deletion.
ORR was superior in atients with any 11q deletion (87% v 29%; p<0.0001) or sole deletion 13q (91% v 62%; p=0.0087) treated with MabCampath compared to chlorambucil. A trend toward improved
ORR was observed in patients with 17p deletion treated with MabCampath (64% v 20%; p=0.0805).MedicinalCompleteremissions were also superior in patients with sole 13q deletion treated with MabCampath
(27% v 0%; p=0.0009). Median PFS was superior in patients with sole 13q deletion treated with MabCampath (24.4 v 13.0 months; p=0.0170 stratified by Rai Stage). A trend towards improved PFS was observed patients with 17p deletion, trisomy 12 and normal karyotype, which did not reach s gnifi ance due to small sample size.
Assessment of CMV by PCR:
In the randomized controlled trial in first line patients (Study 4), patients in the MabCampath arm were tested weekly for CMV using a PCR (polymerase chain reaction) assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. In this study, asymptomatic positive PCR only for CMV was reported in 77/147 (52.4%) of MabCampath-treated patients; symptomatic CMV infection was reported less commonly in 23/147 MabCampath treated patients (16%). In the MabCampath arm 36/77 (46.8%) of patients with asymptomatic PCR positive CMV received antiviral therapy and 47/77 (61%) of these patients had MabCampath therapy interrupted. The presence of asymptomatic positive PCR for CMV or symptomatic PCR positive
14
CMV infection during treatment with MabCampath had no measurable impact on progression free survival (PFS).
|
|
Previously treated B-CLL patients:
|
|
|
|
|
|
|
|
|
|
|
Determination of the efficacy of MabCampath is based on overall response and survival rates. Data
|
|
|
|
|
|
|
|
authorised
|
|
|
|
available from three uncontrolled B-CLL studies are summarised in the following table:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Efficacy parameters
|
Study 1
|
|
Study 2
|
|
|
Study 3
|
|
|
|
Number of Patients
|
93
|
|
32
|
|
|
24
|
|
|
|
|
Diagnostic Group
|
B-CLL pts who had
|
B-CLL pts who had
|
B-CLL (plus a PLL)
|
|
|
|
|
|
received an alkylating
|
failed to respond
|
pts who had failed to
|
|
|
|
|
|
agent and had failed
|
relapsed following
|
resp
|
nd relapsed
|
|
|
|
|
|
fludarabine
|
|
treatment with
|
following treatment
|
|
|
|
|
|
|
|
conventional
|
wi
|
fludarabine
|
|
|
|
|
|
|
|
chemotherapy
|
|
|
|
|
|
|
Median Age (years)
|
66
|
|
57
|
|
|
62
|
|
|
|
|
Disease Characteristics (%)
|
|
|
|
|
|
|
|
|
|
|
Rai Stage III/IV
|
76
|
|
72
|
|
|
71
|
|
|
|
|
B Symptoms
|
42
|
|
longer
|
|
|
21
|
|
|
|
|
|
31
|
|
|
|
|
|
|
Prior Therapies (%):
|
|
|
|
|
|
|
|
|
|
|
Alkylating Agents
|
100
|
|
100
|
|
|
92
|
|
|
|
|
Fludarabine
|
100
|
|
34
|
|
|
100
|
|
|
|
|
Number of Prior Regimens (range)
|
3 (2-7)
|
|
3 (1-10)
|
|
|
3 (1-8)
|
|
|
|
|
Initial Dosing Regimen
|
Gradual escalati
|
|
Gradual escalation
|
Gradual escalation
|
|
|
|
|
|
from 3 to 10 to 30 mg
|
from 10 to 30 mg
|
from 10 to 30 mg
|
|
|
|
|
Final Dosing Regimen
|
30 mg iv 3 x week y
|
30 mg iv 3 x weekly
|
30 mg iv 3 x weekly
|
|
|
|
|
Overall Response Rate (%)
|
33
|
|
21
|
|
|
29
|
|
|
|
|
(95% Confidence Interval)
|
(23 -43)
|
|
(8-33)
|
|
|
(11-47)
|
|
|
|
|
Complete Response
|
2
|
|
0
|
|
|
0
|
|
|
|
|
Partial Response
|
31
|
|
21
|
|
|
29
|
|
|
|
|
Median Duration of Response (months)
|
7
|
|
7
|
|
|
11
|
|
|
|
|
(95% Confidence Interval)
|
(5-8)
|
|
(5-23)
|
|
|
(6-19)
|
|
|
|
|
Median time to Response (months)
|
2
|
|
4
|
|
|
4
|
|
|
|
|
(95% Confidence Interval)
|
(1-2)
|
|
(1-5)
|
|
|
(2-4)
|
|
|
|
|
Progression-Free Survival (m nths)
|
4
|
|
5
|
|
|
7
|
|
|
|
|
(95% Confidence Interval)
|
(3- 5)
|
|
(3- 7)
|
|
|
(3- 9)
|
|
|
|
|
Survival (months):
|
|
|
|
|
|
|
|
|
|
|
(95% Confidence Interval)
|
16 (12-22)
|
|
26 (12-44)
|
|
|
28 (7-33)
|
|
|
|
|
All patients
|
|
|
|
|
|
|
|
Responders
|
33 (26-NR)
|
|
44 (28-NR)
|
|
36 (19-NR)
|
|
|
|
|
Medicinaldecreasedwithrepeated administration
|
due to decreased receptor-mediated clearance
|
(i.e. loss of
|
|
|
|
|
NR = not re ched
|
|
|
|
|
|
|
|
|
5.2 Pharmacokinetic properties
Pharmacokinetics were characterised in MabCampath-naive patients with B-cell chronic lymphocytic leukaemia (B-CLL) who had failed previous therapy with purine analogues. MabCampath was
ministered as 2 hour intravenous infusion, at the recommended dosing schedule, starting at 3 mg and increasing to 30 mg, 3 times weekly, for up to 12 weeks. MabCampath pharmacokinetics followed 2-compartment model and displayed non-linear elimination kinetics. After the last 30 mg dose, the
median volume of distribution at steady-state was 0.15 l/kg (range: 0.1-0.4 l/kg), indicating that distribution was primarily to the extracellular fluid and plasma compartments. Systemic clearance
CD52 receptors in the periphery). With repeated administration and consequent plasma concentration accumulation, the rate of elimination approached zero-order kinetics. As such, half-life was 8 hours (range: 2-32 hours) after the first 30 mg dose and was 6 days (range: 1-14 days) after the last 30 mg
15
dose. Steady-state concentrations were reached after about 6 weeks of dosing. No apparent difference in pharmacokinetics between males and females was observed nor was any apparent age effect observed.
5.3 Preclinical safety data
Preclinical evaluation of alemtuzumab in animals has been limited to the cynomolgusauthorisedmonkeybecause of the lack of expression of the CD52 antigen on non-primate species.
Lymphocytopenia was the most common treatment-related effect in this species. A slight cumulative effect on the degree of lymphocyte depletion was seen in repeated dose studies compared to single dose studies. Lymphocyte depletion was rapidly reversible after cessation of dosing. Reversible neutropenia was seen following daily intravenous or subcutaneous dosing for 30 days, but n t following single doses or daily dosing for 14 days. Histopathology results from bone marrow samples revealed no remarkable changes attributable to treatment. Single intravenous doses of 10 and 30 mg/kg produced moderate to severe dose related hypotension accompanied by a slight tachycardia.
MabCampath Fab binding was observed in lymphoid tissues and the mononucle ph gocyte system. Significant Fab binding was also observed in the male reproductive tract (epididymis, sperm, seminal vesicle) and the skin.
No other findings, in the above toxicity studies, provide information of si nificant relevance to clinical use.
No short or long term animal studies have been conducted with MabCampath to assess carcinogenic and mutagenic potential.
6. PHARMACEUTICAL PARTICULARS
6. 1 List of excipients
Disodium edetate
Polysorbate 80
Potassium chloride
Potassium dihydrogen phosphate
Sodium chloride
Dibasic sodium phosphate
Water for injections
Medicinal6.2Incompatibiities
This medicin product must not be mixed with other medicinal products except those mentioned in sect on 6.6.
There are no known incompatibilities with other medicinal products. However, other medicinal
produ ts should not be added to the MabCampath infusion or simultaneously infused through the same ntravenous line.
6.3 Shelf life
Unopen ampoule:3 years.
Reconstituted solution:MabCampath contains no antimicrobial preservative. MabCampath should be used within 8 hours after dilution. Solutions may be stored at 15°C -30°C or refrigerated. This can only be accepted if preparation of the solution takes place under strictly aseptic conditions and the solution is protected from light.
16
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Clear Type I glass ampoule, containing 3 ml of concentrate.
Pack size: carton of 3 ampoules.
6.6 Special precautions for disposal and other handling
The ampoule contents should be inspected for particulate matter and discolouration prior to administration. If particulate matter is present or the concentrate is coloured, then the mpo le should not be used.
should be prepared for intravenous infusion using aseptic techniques and that the diluted solution for infusion should be administered within 8 hours after preparation and protected from light. The required amount of the ampoule contents should be added, via a sterile, low-protein binding, non-fibre 5 μm filter, to 100 ml of sodium chloride 9 mg/ml (0.9%) s luti for infusion or glucose (5%) solution for infusion. The bag should be inverted gent y to mix the solution. Care should be taken to ensure the sterility of the prepared solution particular y as it c ntains no antimicrobial preservatives.
MabCampath contains no antimicrobial preservatives, therefore,longeritiscomm nded that MabCampath
Other medicinal products should not be added to the MabCampath infusion solution or simultaneously infused through the same intravenous line (see section 4.5).
Caution should be exercised in the handling and preparation of the MabCampath solution. The use of latex gloves and safety glasses is re ommended to avoid exposure in case of breakage of the ampoule or other accidental spillage. Women who are pregnant or trying to become pregnant should not handle MabCampath.
Procedures for proper han ling and isposal should be observed. Any spillage or waste material should be disposed of by incineration.
7. MARKETING AUTHORISATION HOLDER
Genzyme Europe BV
Goo meer 10
1411 DD Naarden
Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/01/193/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 06/07/2001
Date of latest renewal: 10/07/2011
17
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.
18
1. NAME OF THE MEDICINAL PRODUCT
MabCampath 30 mg/ml concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
|
One ml contains 30 mg of alemtuzumab.
|
authorised
|
|
|
|
|
|
Each vial contains 30 mg of alemtuzumab.
|
|
|
Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for 21-28 kD lymphocyte cell surface glycoprotein (CD52). The antibody is produced in mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
4. CLINICAL PARTICULARS
4. 1 Therapeutic indications
MabCampath is indicated for the treatment of patients with B -cell chronic lymphocytic leukaemia (B-CLL) for whom fludarabine combination chem therapy is not appropriate.
4.2 Posologyproductandmethodofadminisraion
MabCampath should be administered under he supervision of a physician experienced in the use of cancer therapy.
Posology
During the first week f eatment, MabCampath should be administered in escalating doses: 3 mg on day 1, 10 mg on day 2 and 30 mg on day 3 assuming that each dose is well tolerated. Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days up to a maximum of 12 weeks.
MedicinalInmostptients,dose escalation to 30 mg can be accomplished in 3-7 days. However, if acute moder te to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills,
rashes a d bronchospasm (some of which may be due to cytokine release) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated before further dose escalation is attempted (see section 4.4).
Median duration of treatment was 11.7 weeks for first-line patients and 9.0 weeks for previously treated patients.
Once patient meets all laboratory and clinical criteria for a complete response, MabCampath should be discontinued and the patient monitored. If a patient improves (i.e. achieves a partial response or stable disease) and then reaches a plateau without further improvement for 4 weeks or more, then MabCampath should be discontinued and the patient monitored. Therapy should be discontinued if there is evidence of disease progression.
19
Concomitant medicinal products
Premedications
Patients should be premedicated with oral or intravenous steroids, an appropriate antihistamine and analgesic 30-60 minutes prior to each MabCampath infusion during dose escalation and as clinically indicated thereafter (see section 4.4).
Prophylactic antibiotics
Antibiotics and antivirals should be administered routinely to all patients throughout and foll wing treatment (see section 4.4).
Dose modification guidelines
There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.
permanently discontinued if autoimmune anaemia or autoimmulongerthrombocytopenia appears. The following table outlines the recommended procedure for d se m dification following the occurrence of haematological toxicity while on therapy:
In the event of serious infection or severe haematological toxicity MabCampath should be interrupted until the event resolves. It is recommended that MabCampath should be int upted in patients whose
platelet count falls to < 25,000/ml or whose absolute neutrophil count (ANC) drops to < 250/ml. MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be
20
|
Haematologic values
|
|
|
Dose modification*
|
|
|
|
|
|
|
|
|
|
|
|
|
ANC < 250/μl and/or platelet count ≤25,000/μl
|
|
|
|
|
|
|
|
|
|
For first occurrence
|
|
Withhold MabCampath therapy. Resume
|
|
|
|
|
MabCampath at 30 mg when ANC ≥ 500/μl and
|
|
|
|
|
platelet count ≥ 50,000/μl.
|
|
|
|
|
|
|
For second occurrence
|
|
Withhold MabCampath therapy. Resume
|
|
|
|
|
MabCampath at 10 mg when ANC ≥ 500/μl and
|
|
|
|
|
platelet count ≥ 50,000/μl.
|
|
|
|
|
|
|
For third occurrence
|
|
Discontinue MabCampath therapy.
|
|
|
|
|
|
≥ 50% decrease from baseline in patients initiating therapy with a baseline ANC ≤ 250/μl and/
|
|
|
baseline platelet count ≤ 25,000/μl
|
|
|
|
|
|
|
|
|
|
For first occurrence
|
|
Withhold MabCampath therapy. Res me
|
|
|
|
|
MabCampath at 30 mg upon ret rn to baseline
|
|
|
|
|
value(s).
|
|
|
|
|
|
|
|
|
|
For second occurrence
|
|
Withhold MabCampath the apy. Resume
|
|
|
|
|
|
|
authorised
|
|
|
|
|
MabCampath at 10 mg upon return to baseline
|
|
|
|
|
value(s).
|
|
|
|
|
|
|
|
|
|
For third occurrence
|
|
Discontinue MabCampath therapy.
|
*If the delay between dosing is ³ 7 days, initiate therapy at MabCampath 3 mg and escalate to 10 mg and then to 30 mg as tolerated
Special populations
Elderly (over 65 years of age)
Recommendationsproductareasstatedabovefor adults. Patients should be monitored carefully (see section 4.4).
Patients with renal or hepatic impairment
No studies have been n ucted.
Paediatric population
The safety and efficacy of MabCampath in children aged less than 17 years of age have not been established. No data are available.
Method of dministration
The MabCampath solution must be prepared according to the instructions provided in section 6.6. All doses should be administered by intravenous infusion over approximately 2 hours.
4.3 Contraindications
- Hypersensitivity to alemtuzumab, to murine proteins or to any of the excipients.
- Active systemic infections.
- HIV.
- Active second malignancies.
- Pregnancy.
4.4 Special warnings and precautions for use
21
Acute adverse reactions, which may occur during initial dose escalation and some of which may be
|
due to the release of cytokines, include hypotension, chills/rigors, fever, shortness of breath and
|
|
|
rashes. Additional reactions include nausea, urticaria, vomiting, fatigue, dyspnoea, headache, pruritus,
|
|
|
diarrhoea and bronchospasm. The frequency of infusion reactions was highest in the first week of
|
|
|
therapy, and declined in the second or third week of treatment, in patients treated with MabCampath
|
|
|
both as first line therapy and in previously treated patients.
|
authorised
|
|
|
|
|
|
If these events are moderate to severe, then dosing should continue at the same level prior to each do e
|
|
|
escalation, with appropriate premedication, until each dose is well tolerated. If therapy is withheld for
|
|
|
more than 7 days, MabCampath should be reinstituted with gradual dose escalation.
|
|
|
|
Transient hypotension has occurred in patients receiving MabCampath. Caution should be used in
|
|
|
treating patients with ischaemic heart disease, angina and/or in patients receiving an anti
|
ypertensive
|
|
|
medicinal product. Myocardial infarction and cardiac arrest have been observed in associa ion with
|
|
|
MabCampath infusion in this patient population.
|
|
|
|
|
Assessment and ongoing monitoring of cardiac function (e.g. echocardiography, he rt
|
te and body
|
|
|
Profound lymphocyte depletion, an expected pharmac longergical effect of MabCampath, inevitably
|
|
|
weight) should be considered in patients previously treated with potentially c
|
diotoxic
|
gents.
|
|
|
It is recommended that patients be premedicated with oral or intravenous st
|
oids 30 - 60 minutes
|
|
prior to each MabCampath infusion during dose escalation and as clinically indicated. Steroids may be discontinued as appropriate, once dose escalation has been achieved. In addition, an oral antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, e.g. paracetamol 500 m , may be given. In the event that acute infusion reactions persist, the infusion time may be exte ded up to 8 hours from the time of reconstitution of MabCampath in solution for infusion .
occurs and may be prolonged. CD4 and CD8 T -cell c unts begin to rise from weeks 8 -12 during treatment and continue to recover for several m ths f ll wing the discontinuation of treatment. In patients receiving MabCampath as first line herapy, the recovery of CD4+ counts to ≥200 cells/µl occurred by 6 months post-treatment, however, at 2 months post-treatment the median was 183
3 times weekly,productorotherphylaxisagainstPneumocystis jiroveci pneumonia (PCP) and an effective oral anti-herpes agent, such as famciclovir, 250 mg twice daily) should be initiated while on therapy and for a minimum of 2 months following completion of treatment with MabCampath or until the CD4+ count has recovered to 200 cells/ml or greater, whichever is the later.
cells/ml. In previously treated patients re eiving MabCampath, the median time to reach a level of 200
cells/ml is 2 months following last inf sion with MabCampath but may take more than 12 months to approximate pretreatment levels. This may predispose patients to opportunistic infections. It is highly recommended that anti-infective prophylaxis (e.g. trimethoprim/sulfamethoxazole 1 tablet twice daily,
MedicinalThepotentiforn increased risk of infection-related complications may exist following treatment with multiple chemotherapeutic or biological agents.
Be ause of the potential for Transfusion Associated Graft Versus Host Disease (TAGVHD) it is re ommended that patients who have been treated with MabCampath receive irradiated blood produ ts.
Asymptomatic laboratory positive Cytomegalovirus (CMV) viraemia should not necessarily be considered serious infection requiring interruption of therapy. Ongoing clinical assessment should be performed for symptomatic CMV infection during MabCampath treatment and for at least 2 months following completion of treatment.
Transient grade 3 or 4 neutropenia occurs very commonly by weeks 5-8 following initiation of treatment. Transient grade 3 or 4 thrombocytopenia occurs very commonly during the first 2 weeks of therapy and then begins to improve in most patients. Therefore, haematological monitoring of patients is indicated. If a severe haematological toxicity develops, MabCampath treatment should be
22
interrupted until the event resolves. Treatment may be reinstituted following resolution of the haematological toxicity (see section 4.2). MabCampath should be permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears.
Complete blood counts and platelet counts should be obtained at regular intervals during MabCampath therapy and more frequently in patients who develop cytopenias.
It is not proposed that regular and systematic monitoring of CD52 expression should be carried out as routine clinical practice. However, if retreatment is considered, it may be prudent to confirm the presence of CD52 expression. In data available from first line patients treated with MabCampath, lo of CD52 expression was not observed around the time of disease progression or death.
Patients may have allergic or hypersensitivity reactions to MabCampath and to murine chimeric monoclonal antibodies.
Medicinal products for the treatment of hypersensitivity reactions, as well as preparedness o institute emergency measures in the event of reaction during administration is necessary (see section 4.2).
disposition and toxicity. In general, older patients (over 65 years of a e) tolerate cytotoxic therapy less well than younger individuals. Since CLL occurs commonly in this older age group, these patients should be monitored carefully (see section 4.2). In the studies in first line and previously treated patients no substantial differences in safety and efficacy re ated to age were observed; however the sizes of the databases are limited.
Males and females of childbearing potential should use effective contraceptive meauthorisedsuresduring
treatment and for 6 months following MabCampath therapy (see sections 4.6 and 5.3).
No studies have been conducted which specifically addresslongertheeffectofa MabCampath
4.5 Interaction with other medicinal products and ther forms of interaction
Although no formal drug interaction studies have been performed with MabCampath, there are no known clinically significant interactions of MabCampath with other medicinal products. Because MabCampath is a recombinant humanized pro ein, a P450 mediated drug-drug interaction would not be expected. However, it is recommended that MabCampath should not be given within 3 weeks of other chemotherapeutic agents.
Although it has not been stu ie , it is recommended that patients should not receive live viral vaccines in, at least, the 12 months f ll wing MabCampath therapy. The ability to generate a primary or anamnestic humoral es onse to any vaccine has not been studied.
4.6 Ferti ity, regnancy and lactation
Pregnancy
MabCampath is contraindicated during pregnancy. Human IgG is known to cross the placental barrier; MabCampath may cross the placental barrier as well and thus potentially cause foetal B and T cell lymphocyte depletion. Animal reproduction studies have not been conducted with MabCampath. It is not known if MabCampath can cause foetal harm when administered to a pregnant woman.
Males and females of childbearing capacity should use effective contraceptive measures during treatment and for 6 months following MabCampath therapy (see section 5.3).
Lactation
It is not known whether MabCampath is excreted in human milk. If treatment is needed, breast-feeding should be discontinued during treatment and for at least 4 weeks following MabCampath therapy.
23
4.8 Undesirable effects
4.7 Effects on ability to drive and use machines
Fertility
There are no definitive studies of MabCampath which assess its impact on fertility. It is not known if MabCampath can affect human reproductive capacity (see section 5.3).
The tables below report adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data.
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
No studies on the effects on the ability to drive and use machines have beenauthorisedperformed.However, caution should be exercised as confusion and somnolence have been reported.
The frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), ncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000). No inform tion available for events that occur at lower frequency, due to the size of the population studied; n=147 for first line treated patients and n=149 for previously treated patients.
The most frequent adverse reactions with MabCampath are: infusion reactions (pyrexia, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnoea), cytope ias (neutropenia, lymphopenia, thrombocytopenia, anaemia), infections (CMV viraemia, CMV i fection, other infections), gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most frequent serious adverse reactions are cyt penias, infusion reactions, and immunosuppression/infections.
Undesirable effects in first line patients
Safety data in first-line B-CLL patients are based on adverse reactions that occurred on study in 147 patients enrolled in a randomized, on rolled s udy of MabCampath as a single agent administered at a dose of 30 mg intravenously three times weekly for up to 12 weeks, inclusive of dose escalation period. Approximately 97% of first-line patients experienced adverse reactions; the most commonly reported reactions in first line patients usually occurred in the first week of therapy.
Within each frequency g uping, undesirable effects observed during treatment or within 30 days following the com letion of treatment with MabCampath are presented in order of decreasing seriousness.
24
|
|
System organ class
|
Very common
|
|
Common
|
Uncommon
|
|
|
|
|
|
|
|
|
|
Infections and
|
Cytomegalovirus
|
|
Pneumonia
|
Sepsis
|
|
|
infestations
|
viraemia
|
|
Bronchitis
|
Staphylococcal
|
|
|
|
Cytomegalovirus
|
|
Pharyngitis
|
bacteraemia
|
|
|
|
infection
|
|
Oral candidiasis
|
Tuberculosis
|
|
|
|
|
|
|
Bronchopneumonia
|
|
|
|
|
|
|
Herpes ophthalmicus
|
|
|
|
|
|
|
Beta haemolytic
|
|
|
|
|
|
|
streptococcal infection
|
|
|
|
|
|
|
Candidiasis
|
|
|
|
|
|
|
Genital candidiasis
|
|
|
|
|
|
|
Urinary tract infecti n
|
|
|
|
|
|
|
Cystitis
|
|
|
|
|
|
|
Body tinea
|
|
|
|
|
|
|
N soph ryngitis
|
|
|
|
|
|
|
Rhinitis
|
|
|
|
|
|
|
|
|
|
Blood and lymphatic
|
|
|
Febrile neutropenia
|
Ag anulocytosis
|
|
|
system disorder
|
|
|
Neutropenia
|
Lymphopenia
|
|
|
|
|
|
Leukopenia
|
Lymphadenopathy
|
|
|
|
|
|
Thrombocytopenia
|
Epistaxis
|
|
|
|
|
|
Anaemia
|
|
|
|
Immune system
|
|
|
|
Anaphylactic reaction
|
|
|
disorders
|
|
|
|
Hypersensitivity
|
|
|
Metabolism and
|
|
|
Weight decreased
|
Tumour lysis syndrome
|
|
|
nutrition disorders
|
|
|
|
Hyperglycaemia
|
|
|
|
|
|
|
Protein total decreased
|
|
|
|
|
|
|
Anorexia
|
|
|
|
|
|
|
|
|
|
Psychiatric disorders
|
|
|
Anxiety
|
|
|
|
Nervous system
|
|
|
Syncope
|
Vertigo
|
|
|
disorders
|
|
|
Dizziness
|
|
|
|
|
|
|
Tremor
|
|
|
|
|
|
|
Paraesthesia
|
|
|
|
|
|
|
Hypoesthesia
|
|
|
|
|
|
|
Headache
|
|
|
|
|
|
|
|
|
|
|
Eye disorders
|
|
|
|
Conjunctivitis
|
|
|
Cardiac disorders
|
|
|
Cyanosis
|
Cardiac arrest
|
|
|
|
|
|
Bradycardia
|
Myocardial infarction
|
|
|
|
|
|
Tachycardia
|
Angina pectoris
|
|
|
|
|
|
Sinus tachycardia
|
Atrial fibrillation
|
|
|
|
|
|
|
Arrhythmia
|
|
|
|
|
|
|
supraventricular
|
|
|
|
|
|
|
Sinus bradycardia
|
|
|
|
|
|
|
Supraventricular
|
|
|
|
|
|
|
extrasystoles
|
|
|
|
|
|
|
|
|
|
Vascular disorders
|
Hypotension
|
|
Hypertension
|
Orthostatic hypotension
|
|
|
|
|
|
|
Hot flush
|
|
|
|
|
|
|
Flushing
|
|
|
Respiratory, thoracic
|
|
|
Bronchospasm
|
Hypoxia
|
|
|
and mediastinal
|
|
|
Dyspnoea
|
Pleural effusion
|
|
|
disorders
|
|
|
|
Dysphonia
|
|
|
|
|
|
|
Rhinorrhoea
|
|
|
|
|
|
|
|
|
|
|
25
|
|
|
|
System organ class
|
Very common
|
Common
|
Uncommon
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Gastrointestinal
|
Nausea
|
Vomiting
|
Ileus
|
|
|
|
|
|
disorders
|
|
Abdominal pain
|
Oral discomfort
|
|
|
|
|
|
|
|
|
Stomach discomfort
|
|
|
|
|
|
|
|
|
Diarrhoea
|
|
|
|
|
|
|
|
|
authorised
|
|
|
|
Skin and subcutaneous
|
Urticaria
|
Dermatitis allergic
|
Rash pruritic
|
|
|
|
|
tissue disorders
|
Rash
|
Pruritus
|
Rash macular
|
|
|
|
|
|
Hyperhidrosis
|
Rash erythematous
|
|
|
|
|
|
Erythema
|
Dermatitis
|
|
|
|
|
|
|
|
|
|
|
|
Musculoskeletal and
|
|
Myalgia
|
Bone pain
|
|
|
|
connective tissue
|
|
Musculoskeletal
|
Arthralgia
|
|
|
|
disorders
|
|
pain
|
Musculoskeletal c est
|
|
|
|
|
|
Back pain
|
pain
|
|
|
|
|
|
|
Muscle spasms
|
|
|
|
Renal and urinary
|
|
|
Urine tp decreased
|
|
|
|
|
disorders
|
|
|
Dys ria
|
|
|
|
General disorders and
|
Fever
|
Fatigue
|
Mucos l inflammation
|
|
|
|
|
administration site
|
Chills
|
Asthenia
|
Infusion site erythema
|
|
|
|
conditions
|
|
|
Localised oedema
|
|
|
|
|
|
|
Infusion site oedema
|
|
|
|
|
|
|
Malaise
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Acute infusion reactions including fever, chills, nausea, v miti g, hypotension, fatigue, rash, urticaria, dyspnoea, headache, pruritus and diarrhoea have been rep rted. The majority of these reactions are mild to moderate in severity. Acute infusion reactions usua y occur during the first week of therapy and substantially decline thereafter. Grade 3 or 4 infusi n reactions are uncommon after the first week of therapy.
Undesirable effects in previously treated pa ie s
Safety data in previously treated B-CLL patients are based on 149 patients enrolled in single-arm studies of MabCampath (Studies 1, 2, and 3). More than 80% of previously treated patients may be expected to experience adverse reactions; the most commonly reported reactions usually occur during the first week of therapy.
Within each frequency g uping, undesirable effects are presented in order of decreasing seriousness.
26
|
|
System organ class
|
Very common
|
Common
|
Uncommon
|
|
|
|
|
|
|
|
|
Infections and
|
Sepsis
|
Cytomegalovirus
|
Bacterial infection
|
|
|
infestations
|
Pneumonia
|
infection
|
|
Viral infection
|
|
|
|
Herpes simplex
|
Pneumocystis jiroveci
|
Fungal dermatitis
|
|
|
|
|
infection
|
|
Laryngitis
|
|
|
|
|
Pneumonitis
|
Rhinitis
|
|
|
|
|
Fungal infection
|
Onychomycosis
|
|
|
|
|
Candidiasis
|
|
|
|
|
|
Herpes zoster
|
|
|
|
|
|
Abscess
|
|
|
|
|
|
|
Urinary tract infection
|
|
|
|
|
|
Sinusitis
|
|
|
|
|
|
|
Bronchitis
|
|
|
|
|
|
Upper respiratory tract
|
|
|
|
|
|
infection
|
|
|
|
|
|
|
Pharyngitis
|
|
|
|
|
|
Infection
|
|
|
|
Neoplasms, benign,
|
|
|
|
Lymphoma – like
|
|
|
malignant and
|
|
|
|
disorder
|
|
|
unspecified (incl. cysts
|
|
|
|
|
|
|
and polyps)
|
|
|
|
|
|
|
Blood and lymphatic
|
Granulocytopenia
|
Febrile
|
eutrope ia
|
Aplasia bone marrow
|
|
|
system disorder
|
Thrombocytopenia
|
Pancytope ia
|
Disseminated
|
|
|
|
Anaemia
|
Leuk pe
|
ia
|
intravascular
|
|
|
|
|
Lymph penia
|
coagulation
|
|
|
|
|
Purpura
|
|
Haemolytic anaemia,
|
|
|
|
|
|
|
Decreased haptoglobin
|
|
|
|
|
|
|
Bone marrow
|
|
|
|
|
|
|
depression
|
|
|
|
|
|
|
Epistaxis
|
|
|
|
|
|
|
Gingival bleeding
|
|
|
|
|
|
|
Haematology test
|
|
|
|
|
|
|
abnormal
|
|
|
|
|
|
|
|
|
|
Immune system
|
|
|
|
Allergic reaction
|
|
|
disorders
|
|
|
|
|
|
|
|
|
|
|
Severe anaphylactic
|
|
|
|
|
|
|
and other
|
|
|
|
|
|
|
hypersensitivity
|
|
|
|
|
|
|
reactions
|
|
|
Metabolism nd
|
Anorexia
|
Hyponatraemia
|
Hypokalaemia
|
|
|
nutrition disorders
|
|
Hypocalcaemia
|
Diabetes mellitus
|
|
|
|
|
Weight decrease
|
aggravated
|
|
|
|
|
Dehydration
|
|
|
|
|
|
Thirst
|
|
|
|
|
|
|
|
|
|
|
Psychiatric disorders
|
|
Confusion
|
Depersonalisation
|
|
|
|
|
Anxiety
|
|
Personality disorder
|
|
|
|
|
Depression
|
Abnormal thinking
|
|
|
|
|
Somnolence
|
Impotence
|
|
|
|
|
Insomnia
|
Nervousness
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
27
|
|
Nervous system
|
Headache
|
|
Vertigo
|
Syncope
|
|
|
disorders
|
|
|
Dizziness
|
Abnormal gait
|
|
|
|
|
|
Tremor
|
Dystonia
|
|
|
|
|
|
Paresthesia
|
Hyperesthesia
|
|
|
|
|
|
Hypoesthesia
|
Neuropathy
|
|
|
|
|
|
Hyperkinesia
|
Taste perversion
|
|
|
|
|
|
Taste loss
|
|
|
|
|
|
|
|
|
|
|
Eye disorders
|
|
|
Conjunctivitis
|
Endophthalmitis
|
|
|
Ear and labyrinth
|
|
|
|
Deafness
|
|
|
disorders
|
|
|
|
Tinnitus
|
|
|
|
|
|
|
|
|
|
Cardiac disorders
|
|
|
Palpitation
|
Cardiac arrest
|
|
|
|
|
|
Tachycardia
|
Myocardial infarcti n
|
|
|
|
|
|
|
Atrial fibrillati n
|
|
|
|
|
|
|
Supraven ricular
|
|
|
|
|
|
|
tachycardia
|
|
|
|
|
|
|
Arrhythmia
|
|
|
|
|
|
|
Br dyc rdia
|
|
|
|
|
|
|
Abnorm l ECG
|
|
|
|
|
|
|
|
|
|
Vascular disorders
|
Hypotension
|
|
Hypertension
|
Pe ipheral ischaemia
|
|
|
|
|
|
Vasospasm
|
|
|
|
|
|
|
Flushing
|
|
|
|
Respiratory, thoracic
|
Dyspnoea
|
|
Hypoxia
|
Stridor
|
|
|
and mediastinal
|
|
|
Haemoptysis
|
Throat tightness
|
|
|
disorders
|
|
|
Br nch spasm
|
Pulmonary infiltration
|
|
|
|
|
|
Coughing
|
Pleural effusion
|
|
|
|
|
|
|
Breath sounds
|
|
|
|
|
|
|
decreased
|
|
|
|
|
|
|
Respiratory disorder
|
|
|
|
|
|
|
|
|
|
Gastrointestinal
|
Vomiting
|
|
Gastrointestinal
|
Gastroenteritis
|
|
|
disorders
|
Nausea
|
|
haemorrhage
|
Tongue ulceration
|
|
|
|
Diarrhoea
|
|
Ulcerative stomatitis
|
Gingivitis
|
|
|
|
|
|
Stomatitis
|
Hiccup
|
|
|
|
|
|
Abdominal pain
|
Eructation
|
|
|
|
|
|
Dyspepsia
|
Dry mouth
|
|
|
|
|
|
Constipation
|
|
|
|
|
|
|
Flatulence
|
|
|
|
Hepatobiliary disorde s
|
|
|
Hepatic function
|
|
|
|
|
|
|
abnormal
|
|
|
|
Skin and subcutaneous
|
Pruritus
|
|
Bullous eruption
|
Maculo-papular rash
|
|
|
tissue disorders
|
Urticaria
|
|
Erythematous rash
|
Skin disorder
|
|
|
|
Rash
|
|
|
|
|
|
|
Hyperhidrosis
|
|
|
|
|
|
|
|
|
|
|
|
|
Mus uloskeletal and
|
|
|
Arthralgia
|
Leg pain
|
|
|
onne tive tissue
|
|
|
Myalgia
|
Hypertonia
|
|
|
sorders
|
|
|
Skeletal pain
|
|
|
|
|
|
|
Back pain
|
|
|
|
|
|
|
|
|
|
|
Renal and urinary
|
|
|
|
Haematuria
|
|
|
disorders
|
|
|
|
Urinary incontinence
|
|
|
|
|
|
|
Urine flow decreased
|
|
|
|
|
|
|
Polyuria
|
|
|
|
|
|
|
Renal function
|
|
|
|
|
|
|
abnormal
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
28
|
|
|
General disorders and
|
Chills
|
Chest pain
|
Pulmonary oedema
|
|
administration site
|
Fever
|
Influenza-like
|
Peripheral oedema
|
|
conditions
|
Fatigue
|
symptoms
|
Periorbital oedema
|
|
|
|
Mucositis
|
Mucosal ulceration
|
|
|
|
Oedema mouth
|
Infusion site bruising
|
|
|
|
Oedema
|
Infusion site dermatitis
|
|
|
|
Asthenia
|
Infusion site pain
|
|
|
|
Malaise
|
|
|
|
|
Temperature change
|
|
|
|
|
sensation
|
|
|
|
|
Infusion site reaction
|
|
|
|
|
Pain
|
|
been reported following MabCampath administration. Theselongersymptomscanbeamelioratedauthorisedavoided if premedication and dose escalation are utilised (see section 4.4).
Undesirable effects observed during post-marketing surveillance
Infusion reactions: Serious and sometimes fatal reactions, including bronchospasm, hypoxia, syncope, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory rrest, myocardial infarction, arrhythmias, acute cardiac insufficiency and cardiac arrest have been observed. Severe anaphylactic and other hypersensitivity reactions, including anaphylactic shock nd ngioedema, have
Infections and infestations: Serious and sometimes fatal viral (e. . adenovirus, parainfluenza, hepatitis B, progressive multifocal leukoencephalopathy (PML)), bacterial (i cluding tuberculosis and atypical
mycobacterioses, nocardiosis), protozoan (e.g. toxoplasma dii), a d fungal (e.g. rhinocerebralmucormycosis)infections,includingthoseduetoreactivatinflatentinfectionshaveoccurred during
post-marketing surveillance. The recommended anti- infective prophylaxis treatment appears to be effective in reducing the risk of PCP and herpes infecti ns (see section 4.4).
EBV-associated lymphoproliferative disorders, in some cases fatal, have been reported.
Blood and lymphatic system disorders: Severe bleeding reactions have been reported.
Immune system disorders: Serio s and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, a toimmune thrombocytopenia, aplastic anaemia, Guillain Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy have been reported. A positive C mbs test has also been observed. Fatal Transfusion Associated Graft Versus Host Disease (TAGVHD) has also been reported.
Metabolism and nutritional disorders: Tumour lysis syndrome with fatal outcome has been reported.
MedicinalNervoussystemdisorders: Intracranial haemorrhage has occurred with fatal outcome, in patients with thrombocytopenia.
Card ac disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported patients previously treated with potentially cardiotoxic agents.
4.9 Overdose
Patients have received repeated unit doses of up to 240 mg of MabCampath. The frequency of grade 3 or 4 adverse events, such as fever, hypotension and anaemia, may be higher in these patients. There is no known specific antidote for MabCampath. Treatment consists of discontinuation of MabCampath and supportive therapy.
29
First line B-CLL patients
5. PHARMACOLOGICAL PROPERTIES
5. 1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC04. Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibodyauthorisedspecificfor
21-28 kD lymphocyte cell surface glycoprotein (CD52) expressed primarily on the surface of normal and malignant peripheral blood B and T cell lymphocytes. Alemtuzumab was generated by the insertion of six complementarity-determining regions from an IgG2a rat monoclonal antibody into a human IgG1 immunoglobulin molecule.
Alemtuzumab causes the lysis of lymphocytes by binding to CD52, a highly expressed, non-modulating antigen which is present on the surface of essentially all B and T cell lymphocytes as well as monocytes, thymocytes and macrophages. The antibody mediates the lysis of lymphocy es via complement fixation and antibody-dependent cell mediated cytotoxicity. The antigen has been found on a small percentage (< 5%) of granulocytes, but not on erythrocytes or platelets. Alemt z mab does not appear to damage haematopoietic stem cells or progenitor cells.
The safety and efficacy of MabCampath were evaluated longerinaPhase3,op-label, randomized comparative trial of first line (previously untreated) Rai stage I-IV B-CLL patients requiring therapy
(Study 4). MabCampath was shown to be superior to chlorambucil as measured by the primary endpoint progression free survival (PFS) (see Figure 1) .
Figure 1: Progression free survival in first ine study (by treatment group)
The secondary objectives included complete response (CR) and overall response (CR or partial response) rates using the 1996 NCIWG criteria, the duration of response, time to alternative treatment and safety of the two treatment arms.
30
Summary of first-line patient population and outcomes
|
|
Independent review of response rate and duration
|
|
|
MabCampath
|
Chlorambucil
|
P value
|
|
|
n=149
|
n=148
|
|
|
Median Age (Years)
|
59
|
60
|
Not Applicable
|
|
Rai Stage III/IV Disease
|
33.6%
|
33.1%
|
Not Applicable
|
|
|
|
|
|
|
Overall Response Rate
|
83.2%
|
55.4%
|
<0.0001*
|
|
Complete Response
|
24.2%
|
2.0%
|
<0.0001*
|
|
MRD negative****
|
7.4%
|
0.0%
|
0.0008*
|
|
Partial Response
|
59.1%
|
53.4%
|
Not Applicable
|
|
Duration of Response**, CR or
|
N=124
|
N=82
|
Not Applicable
|
|
PR (Months)
|
16.2
|
12.7
|
|
|
K-M median (95% Confidence
|
(11.5, 23.0)
|
(10.2, 14.3)
|
|
|
Interval)
|
|
|
|
|
Time to Alternative Treatment
|
23.3
|
14.7
|
0.0001***
|
|
(Months)
|
(20.7, 31.0)
|
(12.6, 16.8)
|
|
|
K-M median (95% Confidence
|
|
|
|
|
Interval)
|
|
|
|
*Pearson chi-square test or Exact test
* Duration of best response
* log-rank test stratified by Rai group (Stage I-II vs III-IV)
* by 4-colour flow
Cytogenetic Analyses in first line B-CLL patie ts:
The cytogenetic profileproductofB-CLLhasbeeni creasi gly recognized as providing important prognosticinformationandmaypredictresponseeraintherapies.Ofthefirst-linepatients(n=282)inwhom
baseline cytogenetic (FISH) data were available in Study 4, chromosomal aberrations were detected in 82%, while normal karyotype was dete ted in 18%. Chromosomal aberrations were categorized according to Döhner’s hierarchical model. In first line patients, treated with either MabCampath or chlorambucil, there were 21 patients with the 17p deletion, 54 patients with 11q deletion, 34 patients with trisomy 12, 51 patients with normal karyotype and 67 patients with sole 13q deletion.
ORR was superior in atients with any 11q deletion (87% v 29%; p<0.0001) or sole deletion 13q (91% v 62%; p=0.0087) treated with MabCampath compared to chlorambucil. A trend toward improved
ORR was observed in patients with 17p deletion treated with MabCampath (64% v 20%; p=0.0805).MedicinalCompleteremissions were also superior in patients with sole 13q deletion treated with MabCampath
(27% v 0%; p=0.0009). Median PFS was superior in patients with sole 13q deletion treated with MabCampath (24.4 v 13.0 months; p=0.0170 stratified by Rai Stage). A trend towards improved PFS was observed patients with 17p deletion, trisomy 12 and normal karyotype, which did not reach s gnifi ance due to small sample size.
Assessment of CMV by PCR:
In the randomized controlled trial in first line patients (Study 4), patients in the MabCampath arm were tested weekly for CMV using a PCR (polymerase chain reaction) assay from initiation through completion of therapy, and every 2 weeks for the first 2 months following therapy. In this study, asymptomatic positive PCR only for CMV was reported in 77/147 (52.4%) of MabCampath-treated patients; symptomatic CMV infection was reported less commonly in 23/147 MabCampath treated patients (16%). In the MabCampath arm 36/77 (46.8%) of patients with asymptomatic PCR positive CMV received antiviral therapy and 47/77 (61%) of these patients had MabCampath therapy interrupted. The presence of asymptomatic positive PCR for CMV or symptomatic PCR positive
31
CMV infection during treatment with MabCampath had no measurable impact on progression free survival (PFS).
|
|
|
Previously treated B-CLL patients:
|
|
|
|
|
|
|
|
|
|
|
|
|
Determination of the efficacy of MabCampath is based on overall response and survival rates. Data
|
|
|
|
|
|
|
|
|
|
authorised
|
|
|
|
|
available from three uncontrolled B-CLL studies are summarised in the following table:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Efficacy parameters
|
|
Study 1
|
|
Study 2
|
|
|
Study 3
|
|
|
|
Number of Patients
|
|
93
|
|
32
|
|
|
24
|
|
|
|
|
Diagnostic Group
|
|
B-CLL pts who had
|
B-CLL pts who had
|
B-CLL (plus a PLL)
|
|
|
|
|
|
|
|
received an alkylating
|
failed to respond
|
pts who had failed to
|
|
|
|
|
|
|
|
agent and had failed
|
relapsed following
|
resp
|
nd relapsed
|
|
|
|
|
|
|
|
fludarabine
|
|
treatment with
|
following treatment
|
|
|
|
|
|
|
|
|
|
conventional
|
wi
|
fludarabine
|
|
|
|
|
|
|
|
|
|
chemotherapy
|
|
|
|
|
|
|
Median Age (years)
|
|
66
|
|
57
|
|
|
62
|
|
|
|
|
Disease Characteristics (%)
|
|
|
|
|
|
|
|
|
|
|
|
Rai Stage III/IV
|
|
76
|
|
72
|
|
|
71
|
|
|
|
|
B Symptoms
|
|
42
|
|
longer
|
|
|
21
|
|
|
|
|
|
|
31
|
|
|
|
|
|
|
Prior Therapies (%):
|
|
|
|
|
|
|
|
|
|
|
|
Alkylating Agents
|
|
100
|
|
100
|
|
|
92
|
|
|
|
|
Fludarabine
|
|
100
|
|
34
|
|
|
100
|
|
|
|
|
Number of Prior Regimens (range)
|
|
3 (2-7)
|
|
3 (1-10)
|
|
|
3 (1-8)
|
|
|
|
|
Initial Dosing Regimen
|
|
Gradual escalati
|
|
Gradual escalation
|
Gradual escalation
|
|
|
|
|
|
|
|
from 3 to 10 to 30 mg
|
from 10 to 30 mg
|
from 10 to 30 mg
|
|
|
|
|
Final Dosing Regimen
|
|
30 mg iv 3 x week y
|
30 mg iv 3 x weekly
|
30 mg iv 3 x weekly
|
|
|
|
|
Overall Response Rate (%)
|
|
33
|
|
21
|
|
|
29
|
|
|
|
|
(95% Confidence Interval)
|
|
(23 -43)
|
|
(8-33)
|
|
|
(11-47)
|
|
|
|
|
Complete Response
|
|
2
|
|
0
|
|
|
0
|
|
|
|
|
Partial Response
|
|
31
|
|
21
|
|
|
29
|
|
|
|
|
Median Duration of Response (months)
|
|
7
|
|
7
|
|
|
11
|
|
|
|
|
(95% Confidence Interval)
|
|
(5-8)
|
|
(5-23)
|
|
|
(6-19)
|
|
|
|
|
Median time to Response (months)
|
|
2
|
|
4
|
|
|
4
|
|
|
|
|
(95% Confidence Interval)
|
|
(1-2)
|
|
(1-5)
|
|
|
(2-4)
|
|
|
|
|
Progression-Free Survival (m nths)
|
|
4
|
|
5
|
|
|
7
|
|
|
|
|
(95% Confidence Interval)
|
|
(3- 5)
|
|
(3- 7)
|
|
|
(3- 9)
|
|
|
|
|
Survival (months):
|
|
|
|
|
|
|
|
|
|
|
|
(95% Confidence Interval)
|
|
16 (12-22)
|
|
26 (12-44)
|
|
|
28 (7-33)
|
|
|
|
|
All patients
|
|
|
|
|
|
|
|
|
Responders
|
|
33 (26-NR)
|
|
44 (28-NR)
|
|
36 (19-NR)
|
|
|
|
|
Medicinaldecreasedwithrepeated administration
|
due to decreased receptor-mediated clearance
|
(i.e. loss of
|
|
|
|
|
NR = not re ched
|
|
|
|
|
|
|
|
|
|
5.2 Pharmacokinetic properties
Pharmacokinetics were characterised in MabCampath-naive patients with B-cell chronic lymphocytic leukaemia (B-CLL) who had failed previous therapy with purine analogues. MabCampath was
ministered as 2 hour intravenous infusion, at the recommended dosing schedule, starting at 3 mg and increasing to 30 mg, 3 times weekly, for up to 12 weeks. MabCampath pharmacokinetics followed 2-compartment model and displayed non-linear elimination kinetics. After the last 30 mg dose, the
median volume of distribution at steady-state was 0.15 l/kg (range: 0.1-0.4 l/kg), indicating that distribution was primarily to the extracellular fluid and plasma compartments. Systemic clearance
CD52 receptors in the periphery). With repeated administration and consequent plasma concentration accumulation, the rate of elimination approached zero-order kinetics. As such, half-life was 8 hours (range: 2-32 hours) after the first 30 mg dose and was 6 days (range: 1-14 days) after the last 30 mg
32
dose. Steady-state concentrations were reached after about 6 weeks of dosing. No apparent difference in pharmacokinetics between males and females was observed nor was any apparent age effect observed.
5.3 Preclinical safety data
Preclinical evaluation of alemtuzumab in animals has been limited to the cynomolgusauthorisedmonkeybecause of the lack of expression of the CD52 antigen on non-primate species.
Lymphocytopenia was the most common treatment-related effect in this species. A slight cumulative effect on the degree of lymphocyte depletion was seen in repeated dose studies compared to single dose studies. Lymphocyte depletion was rapidly reversible after cessation of dosing. Reversible neutropenia was seen following daily intravenous or subcutaneous dosing for 30 days, but n t following single doses or daily dosing for 14 days. Histopathology results from bone marrow samples revealed no remarkable changes attributable to treatment. Single intravenous doses of 10 and 30 mg/kg produced moderate to severe dose related hypotension accompanied by a slight tachycardia.
MabCampath Fab binding was observed in lymphoid tissues and the mononucle ph gocyte system. Significant Fab binding was also observed in the male reproductive tract (epididymis, sperm, seminal vesicle) and the skin.
No other findings, in the above toxicity studies, provide information of si nificant relevance to clinical use.
No short or long term animal studies have been conducted with MabCampath to assess carcinogenic and mutagenic potential.
6. PHARMACEUTICAL PARTICULARS
6. 1 List of excipients
Disodium edetate
Polysorbate 80
Potassium chloride
Potassium dihydrogen phosphate
Sodium chloride
Dibasic sodium phosphate
Water for injections
Medicinal6.2Incompatibiities
This medicin product must not be mixed with other medicinal products except those mentioned in sect on 6.6.
There are no known incompatibilities with other medicinal products. However, other medicinal
produ ts should not be added to the MabCampath infusion or simultaneously infused through the same ntravenous line.
6.3 Shelf life
Unopen vial:3 years.
Reconstituted solution:MabCampath contains no antimicrobial preservative. MabCampath should be used within 8 hours after dilution. Solutions may be stored at 15°C -30°C or refrigerated. This can only be accepted if preparation of the solution takes place under strictly aseptic conditions and the solution is protected from light.
33
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Clear type I glass vial, closed with a rubber stopper, containing 1 ml of concentrate.
Pack size: carton of 3 vials.
6.6 Special precautions for disposal and other handling
The vial contents should be inspected for particulate matter and discolouration prior to dministration.
If particulate matter is present or the concentrate is coloured, then the vial should not be used.
MabCampath contains no antimicrobial preservatives, therefore, it is r comm nded that MabCampath should be prepared for intravenous infusion using aseptic techniques and that the diluted solution for infusion should be administered within 8 hours after preparation and protected from light. The required amount of the vial contents should be added to 100 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose (5%) solution for infusi . The bag should be inverted gently to mixthesolution.Careshouldbetakentoensurethesterilityfthepreparedsolutionparticularlyasit
|
contains no antimicrobial preservatives.
|
longer
|
|
|
|
|
|
Other medicinal products should not be added to the MabCampath infusion solution or simultaneously
|
|
|
infused through the same intravenous line (see section 4.5).
|
|
Caution should be exercised in the handling and preparation of the MabCampath solution. The use of latex gloves and safety glasses is re ommended to avoid exposure in case of breakage of the vial or other accidental spillage. Women who are pregnant or trying to become pregnant should not handle MabCampath.
Procedures for proper han ling and isposal should be observed. Any spillage or waste material should be disposed of by incineration.
7. MARKETING AUTHORISATION HOLDER
Genzyme Europe BV
Goo meer 10
1411 DD Naarden
Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/01/193/002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 06/07/2001
Date of latest renewal: 10/07/2011
34
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.
35
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
36
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer of the biological active substance
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65
D-88397 Biberach an der Riss
Deutschland
Genzyme Flanders bvba
Cipalstraat 8
2440 Geel
Belgium
Name and address of the manufacturer responsible for batch release
Genzyme Ltd.
37 Hollands Road
Haverhill, Suffolk CB9 8PU
United Kingdom
Genzyme Ireland Limited.
IDA Industrial Park
Old Kilmeaden Road
Waterford
Ireland
Bayer Schering Pharma AG
Müllerstrasse 178
D-13342 Berlin
Deutschland
B. CONDITIONS OF THE MARKETING AUTHORISATION
· CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to restricted medical prescription (See Annex 1: Summary of Product Characteristics, section 4.2).
· CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall agree the details of an educational brochure with the National Competent Authorities.
The MAH shall ensure that all doctors who prescribe MabCampath are provided with a healthcare professional information pack containing the following:
· Educational brochure
· Summary of Product Characteristics (SPC) and Package Leaflet and Labelling
37
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Key elements to be included in the educational brochure
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· The risk of opportunistic infections, in particular CMV viraemia
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· Recommendation to avoid vaccination with live vaccines for at least 12 months following
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MabCampath therapy
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· The risk of infusion reactions
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authorised
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Risk Management Plan
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o
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Need for premedication
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o That treatment for hypersensitivity reactions, including measures for resuscitation
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should be available during administration
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o That the risk of infusion reactions is highest in first week of therapy
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o That if the reaction is moderate or severe dosing should continue at the same level (
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no dose escalation) until each dose is well tolerated
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o That if therapy is withheld for more than 7 days then MabCampath should be
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reinstituted with gradual dose escalation
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·
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OTHER CONDITIONS
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The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
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(PSUR).
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longer
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The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
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the Pharmacovigilance Plan, as agreed in version 3.3 of the Risk Mana m nt Plan (RMP) presented
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in Module 1.8.2. of the Marketing Authorisation Application a
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d a y subsequent updates of the RMP
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agreed by the CHMP.
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As per the CHMP Guideline on Risk Management Systems f
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medicinal products for human use, the
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updated RMP should be submitted at the same time as the next Periodic Safety Update Report
In addition, an updated RMP should be submitted:
· When new information is received hat may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities
· Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
· At the request of the EMA
38
ANNEX III
LABELLING AND PACKAGE LEAFLET
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON
1. NAME OF THE MEDICINAL PRODUCT
MabCampath 10 mg/ml concentrate for solution for infusion Alemtuzumab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 10 mg of alemtuzumab.
Each ampoule contains 30 mg of alemtuzumab.
3. LIST OF EXCIPIENTS
Other ingredients: longer
Disodium edetate, polysorbate 80, potassium chloride, potassium dihydro phosphate, sodium chloride, dibasic sodium phosphate, water for injections.
4. PHARMACEUTICAL FORM AND CONTENTS
Concentrate for solution for infusion
3 x 3 ml ampoules
30 mg/3 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet bef re use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Read the leaflet for the shelf life of the reconstituted product.
41
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Any spillage or waste material should be disposed of by incineration.
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Marketing Authorisation Holder:
Genzyme Europe BV, Gooimeer 10, 1411 DD Naarden, Netherlands
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/01/193/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justific tion for not including Braille accepted
42
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS AMPOULE
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
MabCampath 10 mg/ml concentrate for solution for infusion
Alemtuzumab
Intravenous use
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 mg/3 ml
6. OTHER
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING CARTON
1. NAME OF THE MEDICINAL PRODUCT
MabCampath 30 mg/ml concentrate for solution for infusion Alemtuzumab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 30 mg of alemtuzumab.
Each vial contains 30 mg of alemtuzumab.
3. LIST OF EXCIPIENTS
Other ingredients: longer
Disodium edetate, polysorbate 80, potassium chloride, potassium dihydro phosphate, sodium chloride, dibasic sodium phosphate, water for injections.
4. PHARMACEUTICAL FORM AND CONTENTS
Concentrate for solution for infusion
3 x 1 ml vials
30 mg/ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet bef re use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
Read the leaflet for the shelf life of the reconstituted product.
44
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original package in order to protect from light,.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
Any spillage or waste material should be disposed of by incineration.
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Marketing Authorisation Holder:
Genzyme Europe BV, Gooimeer 10, 1411 DD Naarden, Netherlands
12. MARKETING AUTHORISATION NUMBER (S)
EU/1/01/193/002
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justific tion for not including Braille accepted
45
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION
MabCampath 30 mg/ml concentrate for solution for infusion
Alemtuzumab
Intravenous use
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP
4. BATCH NUMBER
Lot
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
30 mg/ml
6. OTHER
46
In this leaflet:
PACKAGE LEAFLET: INFORMATION FOR THE USER
MabCampath 10 mg/ml concentrate for solution for infusion
Alemtuzumab
Read all of this leaflet carefully before you start using this medicine.
· Keep this leaflet. You may need to read it again.
· If you have any further questions, ask your doctor or pharmacist.
· If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
1. What MabCampath is and what it is used for
2. Before you use MabCampath
3. How to use MabCampath
4. Possible side effects
5. How to store MabCampath
lymphocytes (a type of white blood cell). It is used in patientslongerfwhomtreatment combinations including fludarabine (another medicine used in leukaemia) are n t appropriate.
6. Further information
1. WHAT MABCAMPATH IS AND WHAT IT IS USED FOR
MabCampath is used to treat patients with chronic lymph cytic leukaemia (CLL), a cancer of the
The active substance in MabCampath, alemtuzumab, is a monoclonal antibody. A monoclonal antibody is an antibody (a type of protein) that has been designed to recognise and bind to a specific structure (called an antigen) that is found in cer ain cells in the body. In CLL, too many lymphocytes are produced. Alemtuzumab has been designed to bind to a glycoprotein (a protein that is coated with sugar molecules) that is found on the surfa e of lymphocytes. As a result of this binding, the lymphocytes die, and this helps to ontrol the CLL.
2. BEFORE YOU USE MABCAMPATH Do not use MabCam ath if you:
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Medicinal
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·
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are
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ergic to alemtuzumab or to proteins of a similar origin or to any of the other ingredients of
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·
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M bC mp th (see section 6 “Further Information”). Your doctor will inform you accordingly
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h ve
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infection
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have HIV
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have an active second malignancy
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are pregnant (see also “Pregnancy”).
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Take special care with MabCampath:
When you first receive MabCampath, you may experience side effects soon after the first infusions (see section 4 “Possible side effects”). These effects will gradually reduce as treatment is continued.
48
You may also be given
· steroids, antihistamines or analgesics (treatment for fever) to help reduce some of the side effects.
The dosage of MabCampath will not be increased until the effects are reduced.
MabCampath treatment may reduce your natural resistance to infections
· antibiotics and antivirals may be given to provide you with extra protection.
You will be examined for symptoms of a certain type of viral infection calledCMV (cytomegal vi us) during your MabCampath therapy and for at least 2 months afterwards.
Your doctor will monitor you carefully if you
· have heart disease or chest pains and/or you are receiving treatment to red ce high blood pressure, as MabCampath may make these conditions worse.
Patients with these conditions may be at higher risk of a heart attack.
· have been treated in the past with chemotherapieslongerorgeneralmdications that have a high risk of causing heart damage, your doctor may wish to monitor your cardiac function (ECG, heart rate, body weight) while receiving MabCampath.
· have other side effects, most often blood disorders fr m taki MabCampath.
Your doctor will be monitoring the effects of treatment and your progress carefully by examining you and by taking blood samples for ana ysis a regular basis.
· are over 65 years of age as you may be m re i t lerant to the medicine than other patients.
You may experience an allergic or hyperse si ivity reaction to MabCampath solution, especially against the protein contained in it, while he infusion is given to you. Your doctor will treat you for this, if this happens.
Because of the potential for a fatal reaction to transfusion of any blood products following treatment with MabCampath, it is recommen ed that you speak to your doctor regarding the irradiation of blood products prior to eceiving the transfusion. You should inform your doctor if you experience any unusual symptoms after a transfusion.
MabCampath is not recommended in children below 17 years of age or in patients who have kidney or liver disorders.
MedicinalTakigothermedicines
You should form your doctor if you are taking or have recently taken any other medicines, even those not prescribed.
In particular, you should not be given MabCampath within 3 weeks of taking any other anti-cancer agents.
Also, you should not be vaccinated with live viral vaccines during treatment and for at least 12 months after you have finished your treatment. Speak to your doctor before receiving any vaccinations.
Pregnancy
MabCampath must not be administered to patients who are pregnant, therefore if you:
49
Driving or using machines
Breast-feeding
· are pregnant or you think you may be pregnant, you should tell your doctor immediately.
· are a woman of childbearing potential or a fertile man, then you should use effective contraceptive methods before you start treatment, during treatment and for 6 months after treatment.
You should stop breast-feeding when you start your treatment and you should notauthorisedbeginbreast-feeding again until at least 4 weeks after you have finished your treatment and you have consulted your doctor
on the matter.
No studies of the effects of MabCampath on the ability to drive and use machines have been performed. However you should be cautious as confusion and sleepiness have been seen. You ould ask your doctor for advice.
3. HOW TO USE MABCAMPATH
Each time you are given MabCampath, it will take about 2 hours for all the solution to enter your blood.
MabCampath is administered into one of your veins via alongerdrip(seealso‘infomation intended for medical or healthcare professionals’).
MabCampath treatment may continue for up to 12 weeks depending your progress.
During the first week, your doctor will increase the d se of MabCampath slowly to reduce the possibility of you having side effects and to allow your body to tolerate MabCampath better.
If you experienceproductearlysideeffectstheiniial smaller doses may be repeated until the effects go away or reduce. The doctor will carefully monitor you and decide what are the appropriate amounts of
MabCampath to give you during yo whole treatment period.
If more MabCampath is given than recommended
Your doctor will treat y u, as appropriate, if you have any side effects.
4. POSSIBLE SIDE EFFECTS
Like all medicines, MabCampath can cause side effects, although not everybody gets them.
Your doctor may give you other medicines or change your dose to help reduce any side effects (see se t on 2 “Take Special care”).
Serious side effects, including difficulty in breathing, inflammation of the lungs, extreme shortness of breath, fainting, heart attack, low red blood cell and low blood platelet levels, infections, bleeding in the brain (intracranial haemorrhage) have occurred with fatal outcome. Diseases related to an overactive immune system where your immune system attacks your own body can lead to low red blood cells, low blood platelets and/or low white blood cells, and nerve disorders, and these can also be fatal. Tell your doctor immediately if you experience any of these side effects.
In addition, testing indicating the presence of antibodies that may destroy red blood cells (Coombs test) has been reported.
50
Very common side effects (seen in at least 1 in every 10 patients treated in clinical trials):
Usually one or more of these effects happen during the first week after the start of treatment:
· fever, shivering/chills, sweating, nausea (feeling sick), vomiting, low blood pressure, low white/red blood cell levels, infections including pneumonia and blood poisoning, irritation and/or blistering of the mouth region, low blood platelet levels, tiredness, rash, itching, red raised lesions on the skin, shortness of breath, headache, diarrhoea and loss of appetite.
They are usually only mild or moderate problems and they gradually diminish during the course of treatment.
Common side effects (affects 1 to 10 patients in every 100 patients treated in clinical trials):
· high blood pressure, fast or slow heart rate, feeling your heart racing, blood vessel spasm
· becoming red in the face, bruising of the skin
· taste changes
· decreased sense of touch
· dizziness, sensation of spinning, fainting, shaking or trembling movements, feeling restless
· eye inflammation (e.g. conjunctivitis)
· pins and needles or burning sensation of the skin
· abnormal liver function, constipation, indigestion, passing abdominal gas
· inflammation, irritation and/or tightness of the lungs, throat a d/or sinuses, too little oxygen reaching the body organs, coughing, coughing up of blood
· abdominal bleeding (e.g. in the stomach and intestine)
· injection site reactions including redness, swelling, pain, bruising, inflammation
· generally feeling unwell, weakness, pain in vari us parts of the body (muscle, back, chest, bones, joints, stomach and intestine)
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weight loss, dehydration, thirst, swelli g f the l wer legs, temperature change sensation, low
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calcium or sodium blood levels
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flu-like symptoms
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abscess, skin redness or allergic skin reaction, blistering of the skin
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confusion, anxiety, depression, sleeplessness
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Uncommon side effects (affects 1 to 10 patients in every 1,000 patients treated in clinical trials):
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bone marrow dis de s
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heart disorde s (hea stopping, heart attack, heart congestion, irregular heart rate)
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blood disorders (abnormal clotting, decreased protein, low potassium levels)
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Medicinal
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high b ood sugar, worsening diabetes
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bleeding ndproductinflammationofthegums, blisters on the tongue, nosebleeds
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fluid
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the lungs, difficulty breathing, harsh sound when breathing, runny nose, abnormal
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f di
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gs in the lungs, lymph gland disorders
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ervousness, abnormal thinking
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swelling around the eye
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ringing sound in the ears, deafness
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hiccups, burping
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hoarseness
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abnormal kidney function
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paralysis of the small bowel
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impotence
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unsteadiness, increased muscle tone
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unusual increased or altered sensitivity to touch
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abnormal sensation/feeling or movement
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51
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Store in the original packaging in order to protect from light.
Do not freeze.
Store in a refrigerator (2°C-8°C).
Keep out of the reach and sight of children.
· pain when urinating, decreases in urine flow, increased frequency in urination, blood in urine, incontinence
· tumour lysis syndrome (a metabolic disorder, which may begin with pains in the side and blood in the urine)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or your pharmacist.
5. HOW TO STORE MABCAMPATH
Do not use MabCampath after the expiry date (EXP) which is stated on the outerauthorisedcartonande ampoule label. The expiry date refers to the last day of that month.
MabCampath should be used within 8 hours after dilution. During that time the solution may be stored at 15°C-30°C or refrigerated.
Do not use MabCampath if you notice any signs of particu ate matter or discolouration prior to administration.
Medicines should not be disposed of via wastewater r h usehold waste. Your healthcare professional will dispose of medicines no longer required. These measures will help protect the environment.
6. FURTHER INFORMATION What MabCampath contains
The active substance is alemtuzumab.
One ml contains 10 mg f alemtuzumab. Each ampoule contains 30 mg of alemtuzumab.
The other ingredients are disodium edetate, polysorbate 80, potassium chloride, potassium dihydrogen phosphate, sodium chloride, dibasic sodium phosphate and water for injections.
MedicinalWhatbCmpath looks like and contents of the pack
MabCampath is a concentrate for solution for infusion that comes in a glass ampoule.
Ea h pack of MabCampath contains 3 ampoules.
Marketing Authorisation Holder
Genzyme Europe BV, Gooimeer 10, 1411 DD Naarden, Netherlands
Manufacturer
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom
Genzyme Ireland Limited., IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland
52
Bayer Schering Pharma AG, Müllerstrasse 178, D-13342 Berlin, Germany.
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.
België/Belgique/Belgien/ Luxemburg/ Luxembourg Genzyme Belgium N.V., Tél/Tel: + 32 2 714 17 11
България
Джензайм ЕООД
Тел. +359 2 971 1001
Česká Republika/Slovenská Republika/ Slovenija
Genzyme Czech s.r.o.
Tel: +420 221 722 511
Danmark/Norge/Sverige/Suomi/Finland/ Ísland
Genzyme A/S, (Danmark/Tanska/Danmörk), Tlf/Puh./Sími: + 45 32712600
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Ελλάδα/Κύπρος
Genzyme Hellas Ltd. (Ελλάδα)
Τηλ: +30 210 99 49 270
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
Th s leaflet was last approved in
Italia/Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349 811
Magyarország
Genzyme Europe B.V. Képviselet Tel: +36 1 310 7440
Nederland
Genzyme Europe B.V.,
Tel: +31 35 699 1200
Österreichlonger Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Polska/Eesti/Latvija/Lietuva Genzyme P ska Sp. z .o. (P la/P lija/Lenkija),
Tel: + 48 22 246 0900
Portugal
Genzyme Portugal S.A.
Tel: +351 21 422 0100
România
Genzyme Biopharma SRL
Tel: +40 212 43 42 28
United Kingdom/Ireland
Genzyme Therapeutics Ltd. (United
Kingdom),
Tel: +44 1865 405200
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
53
The following information is intended for medical or healthcare professionals only:
During the first week, 3 mg of MabCampath is given on Day 1, then 10 mg on Day 2 and then 30 mg on Day 3, depending on tolerability. MabCampath will be given at 30 mg three times per calendar week on alternate days, for up to 12 weeks.
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infused though the same intravenous line.
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authorised
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The ampoule contents should be inspected for particulate matter and discolouration prior to
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administration. If particulate matter is present or the solution is coloured, then the ampoule should not
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be used.
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MabCampath contains no antimicrobial preservatives, therefore, it is recommended that MabCampath
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should be prepared for intravenous infusion using aseptic techniques and that the diluted soluti
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n f
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infusion should be administered within 8 hours after preparation and protected from light. The
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required amount of the ampoule contents should be added, via a sterile, low-protein binding, n
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n-fibre
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5 μm filter, to 100 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion or glucose (5%)
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solution for infusion. The bag should be inverted gently to mix the solution. Care sho
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ld be aken to
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ensure the sterility of the prepared solution particularly as it contains no antimicrobial preservatives.
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Other medicinal products should not be added to the MabCampath infusion solution
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simultaneously
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longer
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Caution should be exercised in the handling and preparation of the MabCampath solution. The use of
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latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the ampoule
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or other accidental spillage. Women who are pregnant or tryi to become pregnant should not handle
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MabCampath.
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Procedures for proper handling and disposal should be
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bserved. Any spillage or waste material
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should be disposed of by incineration.
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54
In this leaflet:
PACKAGE LEAFLET: INFORMATION FOR THE USER
MabCampath 30 mg/ml concentrate for solution for infusion
Alemtuzumab
Read all of this leaflet carefully before you start using this medicine
· Keep this leaflet. You may need to read it again.
· If you have any further questions, ask your doctor or pharmacist.
· If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
1. What MabCampath is and what it is used for
2. Before you use MabCampath
3. How to use MabCampath
4. Possible side effects
5. How to store MabCampath
lymphocytes (a type of white blood cell). It is used in patientslongerfwhomtreatment combinations including fludarabine (another medicine used in leukaemia) are n t appropriate.
6. Further information
1. WHAT MABCAMPATH IS AND WHAT IT IS USED FOR
MabCampath is used to treat patients with chronic lymph cytic leukaemia (CLL), a cancer of the
The active substance in MabCampath, alemtuzumab, is a monoclonal antibody. A monoclonal antibody is an antibody (a type of protein) that has been designed to recognise and bind to a specific structure (called an antigen) that is found in cer ain cells in the body. In CLL, too many lymphocytes are produced. Alemtuzumab has been designed to bind to a glycoprotein (a protein that is coated with sugar molecules) that is found on the surfa e of lymphocytes. As a result of this binding, the lymphocytes die, and this helps to ontrol the CLL.
2. BEFORE YOU USE MABCAMPATH Do not use MabCam ath if you:
|
·
|
are
|
ergic to alemtuzumab or to proteins of a similar origin or to any of the other ingredients of
|
|
|
Medicinal
|
|
|
·
|
M bC mp th (see section 6 “Further Information”). Your doctor will inform you accordingly
|
|
|
h ve
|
infection
|
|
|
·
|
have HIV
|
|
|
·
|
have an active second malignancy
|
|
|
·
|
are pregnant (see also “Pregnancy”).
|
|
Take special care with MabCampath:
When you first receive MabCampath, you may experience side effects soon after the first infusions (see section 4 “Possible side effects”). These effects will gradually reduce as treatment is continued.
You may also be given
· steroids, antihistamines or analgesics (treatment for fever) to help reduce some of the side effects.
55
The dosage of MabCampath will not be increased until the effects are reduced.
MabCampath treatment may reduce your natural resistance to infections
|
·
|
antibiotics and antivirals may be given to provide you with extra protection.
|
|
|
You will be examined for symptoms of a certain type of viral infection called CMV (cytomegalovirus)
|
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during your MabCampath therapy and for at least 2 months afterwards.
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Your doctor will monitor you carefully if you
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have heart disease or chest pains and/or you are receiving treatment to reduce high bl
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pressure, as MabCampath may make these conditions worse.
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Patients with these conditions may be at higher risk of a heart attack.
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have been treated in the past with chemotherapies or general medications that have high risk
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of causing heart damage, your doctor may wish to monitor your cardiac function (ECG, heart
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rate, body weight) while receiving MabCampath.
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authorised
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have other side effects, most often blood disorders from taking MabCampath.
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Your doctor will be monitoring the effects of treatment and your progr ss carefully by
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examining you and by taking blood samples for analysis a re ular basis.
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are over 65 years of age as you may be more intolera t to the medicine than other patients.
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You may experience an allergic or hypersensitivity reactionlongertoMabCampath solution, especially against the protein contained in it, while the infusinoisgiven to you. Your doctor will treat you for this, if this happens.
Because of the potentialproductforafatalreacion ra sfusion of any blood products following treatment with MabCampath, it is recommended hat you speak to your doctor regarding the irradiation of
blood products prior to receiving the transfusion. You should inform your doctor if you experience any unusual symptoms after a transf sion.
MabCampath is not recommen ed in children below 17 years of age or in patients who have kidney or liver disorders.
Taking other medicines
You should inform your doctor if you are taking or have recently taken any other medicines, even those not prescribed.
In part cular, you should not be given MabCampath within 3 weeks of taking any other anti-cancer age ts.
Also, you should not be vaccinated with live viral vaccines during treatment and for at least 12 months after you have finished your treatment. Speak to your doctor before receiving any vaccinations.
Pregnancy
MabCampath must not be administered to patients who are pregnant, therefore if you:
· are pregnant or you think you may be pregnant, you should tell your doctor immediately.
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Driving or using machines
· are a woman of childbearing potential or a fertile man, then you should use effective contraceptive methods before you start treatment, during treatment and for 6 months after treatment.
Breast-feeding
You should stop breast-feeding when you start your treatment and you should notauthorisedbeginbreast-feeding
again until at least 4 weeks after you have finished your treatment and you have consulted your doctor on the matter.
No studies of the effects of MabCampath on the ability to drive and use machines have been performed. However you should be cautious as confusion and sleepiness have been seen. Y s uld ask your doctor for advice.
3. HOW TO USE MABCAMPATH
MabCampath is administered into one of your veins via longeradrip(seealso‘infomation intended for medical or healthcare professionals’).
Each time you are given MabCampath, it will take about 2 hours for all the solution to enter your blood.
MabCampath treatment may continue for up to 12 weeks depending your progress.
During the first week, your doctor will increase the d se of MabCampath slowly to reduce the possibility of you having side effects and to all w y ur b dy to tolerate MabCampath better.
If you experience early side effects the ini ial smaller doses may be repeated until the effects go away or reduce. The doctor will carefully moni or you and decide what are the appropriate amounts of MabCampath to give you during your whole treatment period.
If more MabCampath is given than recommended
Your doctor will treat y u, as appropriate, if you have any side effects.
4. POSSIBLE SIDE EFFECTS
Like all medicines, MabCampath can cause side effects, although not everybody gets them.
Your doctor m y give you other medicines or change your dose to help reduce any side effects (see sect on 2 “Take Special care”).
Ser ous side effects, including difficulty in breathing, inflammation of the lungs, extreme shortness of breath, fainting, heart attack, low red blood cell and low blood platelet levels, infections, bleeding in the brain (intracranial haemorrhage) have occurred with fatal outcome. Diseases related to an overactive immune system where your immune system attacks your own body can lead to low red blood cells, low blood platelets and/or low white blood cells, and nerve disorders, and these can also be fatal. Tell your doctor immediately if you experience any of these side effects.
In addition, testing indicating the presence of antibodies that may destroy red blood cells (Coombs test) has been reported.
Very common side effects (seen in at least 1 in every 10 patients treated in clinical trials):
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Usually one or more of these effects happen during the first week after the start of treatment:
· fever, shivering/chills, sweating, nausea (feeling sick), vomiting, low blood pressure, low white/red blood cell levels, infections including pneumonia and blood poisoning, irritation and/or blistering of the mouth region, low blood platelet levels, tiredness, rash, itching, red raised lesions on the skin, shortness of breath, headache, diarrhoea and loss of appetite.
They are usually only mild or moderate problems and they gradually diminish during the course of treatment.
Common side effects (affects 1 to 10 patients in every 100 patients treated in clinical trials):
· high blood pressure, fast or slow heart rate, feeling your heart racing, blood vessel spasm
· becoming red in the face, bruising of the skin
· taste changes
· decreased sense of touch
· dizziness, sensation of spinning, fainting, shaking or trembling movements, feeling restless
· eye inflammation (e.g. conjunctivitis)
· pins and needles or burning sensation of the skin
· abnormal liver function, constipation, indigestion, passing abdominal gas
· inflammation, irritation and/or tightness of the lungs, throat and/or sinus s, too little oxygen reaching the body organs, coughing, coughing up of blood
· abdominal bleeding (e.g. in the stomach and intestine)
· injection site reactions including redness, swelling, pain, bruising, inflammation
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generally feeling unwell, weakness, pain in various parts f the body (muscle, back, chest,
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bones, joints, stomach and intestine)
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weight loss, dehydration, thirst, swelling f the l wer legs, temperature change sensation, low
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calcium or sodium blood levels
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flu-like symptoms
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product
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abscess, skin redness or allergic skin reaction, blistering of the skin
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confusion, anxiety, depression, sleeplessness
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Uncommon side effects (affects 1 to 10 in every patients in 1,000 patients treated in clinical trials):
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bone marrow dis rders
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heart disorde s (hea st pping, heart attack, heart congestion, irregular heart rate)
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blood disorde s (abno mal clotting, decreased protein, low potassium levels)
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high b ood sugar, worsening diabetes
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Medicinal·unsteadiness, increased muscle tone
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bleeding and inflammation of the gums, blisters on the tongue, nosebleeds
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fluid
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the ungs, difficulty breathing, harsh sound when breathing, runny nose, abnormal
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ervousness, abnormal thinking
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swelli
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ringing sound in the ears, deafness
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hiccups, burping
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hoarseness
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abnormal kidney function
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paralysis of the small bowel
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impotence
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· unusual increased or altered sensitivity to touch’
· abnormal sensation/feeling or movement
· pain when urinating, decreases in urine flow, increased frequency in urination, blood in urine, incontinence
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· tumour lysis syndrome (a metabolic disorder, which may begin with pains in the side and blood in the urine)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or your pharmacist.
5. HOW TO STORE MABCAMPATH
Keep out of the reach and sight of children.
Do not use MabCampath after the expiry date (EXP) which is stated on the outer carton and the vial label. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in the original packaging in order to protect from light.
MabCampath should be used within 8 hours after dilution. During that time the solution may be stored at 15°C-30°C or refrigerated.
Do not use MabCampath if you notice any signs of particulate matter or discolouration prior to administration.
Medicines should not be disposed of via wastewater or h useh ld waste. Your healthcare professional will dispose of medicines no longer required. These measures will help protect the environment.
6. FURTHER INFORMATION What MabCampath contains
The active substance is alemtuz mab.
One ml contains 30 mg of alemtuzumab. Each vial contains 30 mg of alemtuzumab.
The other ingredients a e dis dium edetate, polysorbate 80, potassium chloride, potassium dihydrogen phosphate, sodium chlo ide, dibasic sodium phosphate and water for injections.
What MabCam ath looks like and contents of the pack
MabC mp th is concentrate for solution for infusion that comes in a glass vial.
Ea h pack of MabCampath contains 3 vials.
Marketing Authorisation Holder
Genzyme Europe BV, Gooimeer 10, 1411 DD Naarden, Netherlands
Manufacturer
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom
Genzyme Ireland Limited., IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland
Bayer Schering Pharma AG, Müllerstrasse 178, D-13342 Berlin, Germany.
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For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.
België/Belgique/Belgien/ Luxemburg/ Luxembourg Genzyme Belgium N.V., Tél/Tel: + 32 2 714 17 11
България
Джензайм ЕООД
Тел. +359 2 971 1001
Česká Republika/Slovenská Republika/ Slovenija
Genzyme Czech s.r.o.
Tel: +420 221 722 511
Danmark/Norge/Sverige/Suomi/Finland/ Ísland
Genzyme A/S, (Danmark/Tanska/Danmörk), Tlf/Puh./Sími: + 45 32712600
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Ελλάδα/Κύπρος
Genzyme Hellas Ltd. (Ελλάδα)
Τηλ: +30 210 99 49 270
España
sanofi-aventis, S.A.
Tel: +34 93 485 94 00
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
This le flet w s last approved in
Italia/Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349 811
Magyarország
Genzyme Europe B.V. Képviselet Tel: +36 1 310 7440
Nederland
Genzyme Europe B.V.,
Tel: +31 35 699 1200
Österreich
GenzymelongerAustriaGmbH, Tel: + 43 1 774 65 38
Polska/Eesti/Latvija/Lietuva Genzyme P lska Sp. z .o. (Poo a/P ija/Lenkija), Tel: + 48 22 246 0900
P rtugal
Ge zyme Portugal S.A.
Tel: +351 21 422 0100
România
Genzyme Biopharma SRL
Tel: +40 212 43 42 28
United Kingdom/Ireland
Genzyme Therapeutics Ltd. (United
Kingdom),
Tel: +44 1865 405200
Deta led formation on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
The following information is intended for medical or healthcare professionals only:
During the first week, 3 mg of MabCampath is given on Day 1, then 10 mg on Day 2 and then 30 mg on Day 3, depending on tolerability. MabCampath will be given at 30 mg three times per calendar week on alternate days, for up to 12 weeks.
The vial contents should be inspected for particulate matter and discolouration prior to administration.
If particulate matter is present or the solution is coloured, then the vial should not be used.
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MabCampath contains no antimicrobial preservatives, therefore, it is recommended that MabCampath should be prepared for intravenous infusion using aseptic techniques and that the diluted solution for
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infusion should be administered within 8 hours after preparation and protected from light. The
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required amount of the vial contents should be added to 100 ml of sodium chloride 9 mg/ml (0.9%)
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solution for infusion or glucose (5%) solution for infusion. The bag should be inverted gently to mix
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the solution. Care should be taken to ensure the sterility of the prepared solution particularly as it
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contains no antimicrobial preservatives.
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authorised
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Other medicinal products should not be added to the MabCampath infusion solution or simultaneously
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infused though the same intravenous line.
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Caution should be exercised in the handling and preparation of the MabCampath solution. The use f latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial other accidental spillage. Women who are pregnant or trying to become pregnant should not andle MabCampath.
Procedures for proper handling and disposal should be observed. Any spillage or waste material should be disposed of by incineration.
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