(and dosage form):
Solution for intravenous infusion
Each ampoule contains 30 mg alemtuzumab (10 mg/mL concentrate solution).
A. 26 Cytostatic agents.
Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for a 21 to 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 antigen has also been found on a small percentage (<5%) of granulocytes, but not on erythrocytes or platelets. The antibody mediates the lysis of lymphocytes via complement fixation and antibody-dependent cell mediated cytotoxicity. Alemtuzumab does not appear to damage haematopoietic stem cells or progenitor cells.
The pharmacokinetics of alemtuzumab were studied in patients who received MabCampath once weekly for a maximum of 12 weeks. Following single intravenous infusions of 7,5 mg, 24 mg or 75 mg, the maximum serum concentration (Cmax) and the area under the curve (AUC) showed relative dose proportionality. The median half-life ranged from ~ 23 to 30 hours.
The pharmacokinetics and pharmacodynamics profile of MabCampath administered as a 30 mg intravenous infusion 3 times per week was evaluated in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia patients who were treated for a maximum of 12 weeks. In patients with chronic lymphocytic leukaemia, peak and trough levels of MabCampath rose during the first few weeks of treatment and then approached steady state by approximately week 6. The rise in serum concentration corresponded with a marked reduction in lymphocytosis. Patients with peripheral lymphocyte counts of >30 000/microL at baseline had significantly lower peak and trough levels of MabCampath during the first 4 to 5 weeks of treatment compared to those with lymphocyte counts <30 000 microL. This suggests that lymphocytosis represents a compartment in the blood in which MabCampath is concentrated.
MabCampath is indicated for the treatment of patients with chronic lymphocytic leukaemia who have been treated with alkylating agents and who have failed to achieve a complete or partial response or who achieved only a short remission (less than 6 months) following fludarabine phosphate therapy.
Acute adverse reactions may occur during initial dose escalation due to the release of cytokines and include hypotension, rigors, fever, shortness of breath, chills and rashes. If these events are moderate to severe, then dosing should continue at the same level with appropriate premedication, until each dose is well tolerated (eg infusion-related toxicities are <grade 2). See “Dosage and directions for use” for dose adjustments and/or discontinuation of treatment. 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 antihypertensive medication.
It is recommended that patients be premedicated with an oral antihistamine and an analgesic 30 minutes prior to first MabCampath treatment at 3 mg, at each subsequent dose escalation, and thereafter, if clinically indicated. The recommended premedication is per oral 50 mg diphenhydramine and 500 mg paracetamol. In cases where severe infusion-related events prevent escalation of the dose, pre-treatment with intravenous (iv) 200 mg hydrocortisone may be useful in decreasing infusion-related reactions.
Profound lymphocyte depletion inevitably occurs and may be prolonged. CD4 and CD8 lymphocyte counts begin to rise following the discontinuation of treatment, but may not return to baseline levels for periods of longer than a year. This may predispose patients to opportunistic infections such as tuberculosis, acute bacterial pneumonia and septicaemia. It is highly recommended that anti-infective prophylaxis against Pneumocystis carinii pneumonia and an oral anti-herpes agent should be initiated while on therapy, and administered up to a minimum of 2 months following cessation of MabCampath treatment. If severe or serious infection does occur, MabCampath treatment should be discontinued until the event has resolved. MabCampath treatment may be reinstituted following resolution of the event.
|Grade 3 or 4 neutropenia occurs very commonly by weeks 5 to 8 following initiation of treatment. Grade 3 or 4 thrombocytopenia occurs very commonly during the first 2 weeks of therapy and then begins to improve in most patients. Therefore, close haematological monitoring of patients is indicated. If severe haematological toxicity develops, MabCampath treatment should be discontinued until the event resolves. MabCampath treatment may be reinstituted following resolution of the haematological toxicity (see “Dosage and directions for use”).|
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.
Patients may have allergic or hypersensitivity reactions to MabCampath and to murine or chimeric monoclonal antibodies.
Males and females of childbearing potential should use effective contraceptive measures during treatment and for 6 months following MabCampath therapy.
No studies have been conducted which specifically address the effect of age on MabCampath disposition and toxicity. In general, older patients (over 65 years of age) tolerate cytotoxic therapy less well than younger individuals. Since chronic lymphocytic leukaemia occurs commonly in this older age group, these patients should be monitored carefully (see “Dosage and directions for use”).
No formal drug interaction studies have been performed with MabCampath. There are no known clinically significant interactions of MabCampath with other medicinal products. 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 response to any vaccine has not been studied.
PREGNANCY AND LACTATION
DOSAGE AND DIRECTIONS FOR USE
MabCampath should be administered under the supervision of a physician experienced in the use of cancer therapy.
Patients should be premedicated with an appropriate antihistamine and analgesic prior to the first dose, at each escalation, and prior to subsequent infusions, as clinically indicated (see “Warnings”).
Antibiotics and antivirals should be administered routinely to all patients throughout and following treatment (see “Warnings”).
During the first week of treatment, 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 (eg infusion-related toxicities are < grade 2). Thereafter, the recommended dose is 30 mg daily administered 3 times weekly on alternate days, up to a maximum of 12 weeks.
In most patients, dose escalation to 30 mg can be accomplished in 3 to 7 days. However, if acute severe adverse reactions (especially hypotension, rigors, fever and bronchospasm) occur at either the 3 mg or 10 mg dose levels, then those doses should be repeated daily until they are well tolerated prior to further escalation (see “Warnings”).
The majority of major responses to MabCampath have been achieved with treatment durations of 4 to 12 weeks. Once a patient meets all laboratory and clinical criteria for a complete response, MabCampath should be discontinued and the patient monitored. If a patient improves (ie 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.
In the event of serious infection or severe haematological toxicity, MabCampath should be discontinued until the event resolves. It is recommended that MabCampath should be discontinued in patients whose platelet count fills to <25 000/microL or whose absolute neutrophil count (ANC) drops to <250/microL. MabCampath may be reinstituted after the infection or toxicity has resolved. The following table outlines the recommended procedure for dose modification following the occurrence of haematological toxicity while on therapy:
(platelets <25 000/ microL and/or ANC <250/microL)
|Reinstitution of MabCampath|
|First occurrence||After resolution, reinstitute at 30 mg *|
|Second occurrence||After resolution, reinstitute at 10 mg *|
|Third occurrence||Permanent discontinuation|
* If therapy has been withheld for more than 7 days, MabCampath must be reinstituted by gradual dose escalation.
Children and adolescents (below 17 years of age):
No studies have been conducted (see “Contra-indications”).
Elderly (over 65 years of age):
Recommendations are as stated above for adults. Patients should be monitored carefully (see “Warnings”).
Patients with renal or hepatic impairment:
Treatment with MabCampath is not recommended (see “Warnings”).
All doses should be administered by intravenous infusion over approximately 2 hours.
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 ampoule should not be used.
MabCampath contains no antimicrobial preservatives, therefore it is recommended that it should be prepared using aseptic techniques and that the diluted solution for infusion should be administered immediately or within 8 hours after preparation. The required amount of the ampoule contents should be added, via a sterile, low-protein binding, non-fibre 5 micron filter, to 100 mL of 0,9% sodium chloride solution or 5% glucose solution. The bag should be inverted gently to mix the solution.
This medicinal product should not be reconstituted with solvents other than sodium chloride and glucose solution.
There are no known incompatibilities with other medicinal products.
Other medicinal products should not be added to the MabCampath infusion solution or simultaneously infused through the same intravenous line.
Women who are pregnant or planning pregnancy should not handle MabCampath.
Procedures for proper handling and disposal should be observed. Any spillage or waste material should be disposed of by incineration.
Caution should be exercised in the handling and preparation of the MabCampath solution. The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the ampoule or other accidental spillage.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
More than 80% of patients may be expected to experience adverse reactions; the most commonly reported reactions usually occurring during the first week of therapy.
Reactions reported have been acute infusion-related reactions including fever, rigors, nausea, vomiting, hypotension, fatigue, rash, urticaria, dyspnoea, headache, pruritus and diarrhoea. The majority of these reactions are mild to moderate in severity. Acute infusion-related reactions usually occur during the first week of therapy and decline substantially thereafter. Grade 3 or 4 infusion-related reactions are uncommon after the first week of therapy. These symptoms can be ameliorated or avoided if premedication and dose escalation are utilised (see “Warnings”).
Grade 3 or 4 infections have been reported, including herpes simplex and pneumonia of grade 3 or 4 severity. Opportunistic infections including Pneumocystis carinii pneumonia, cytomegalovirus, Aspergillus pneumonia and herpes zoster occur. Rhinocerebral mucormycosis has been reported. None of the patients with Pneumocystis carinii pneumonia or herpes zoster had received the anti-infective prophylaxis. Such therapy appears to be effective in reducing the risk of infections due to these opportunistic pathogens (see “Warnings”).
Severe bleeding reactions have been reported. One patient developed fatal idiopathic thrombocytopenic purpura following MabCampath therapy. Pancytopenia has been reported and may be grade 3 or 4 in severity or serious in nature. A positive Coombs test is observed; clinically apparent haemolysis has not been reported in patients treated to date.
The table below reports adverse reactions by body system and in descending order of severity:
|Body system||Adverse reactions and infections|
(>1% to 10%)
(>0,1% to 1%)
|Application site||Injection site reaction||Injection site bruising
Injection site dermatitis
Injection site pain
|Body as a whole –general||Rigors
Temperature change sensation
|Central and peripheral nervous including vision, hearing and special senses||Headache||Taste loss
|Gastro-intestinal, liver and biliary||Vomiting
Hepatic function abnormal
|Aplasia bone marrow
|Metabolic and nutritional||Hyponatraemia
Upper tract infection
Breath sounds decreased
|Skin and appendages||Urticaria
|Urinary||Urinary tract infection||Renal function abnormal
Urine flow decreased.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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 overdosage. Treatment consists of discontinuation of MabCampath and supportive therapy.
Each cardboard carton contains 3 x 5 mL clear glass ampoules each with 3 mL concentrate.
Store at 2 to 8°C in a refrigerator. Do not freeze. Protect from light. Do not remove from the outer container until immediately before use. Keep out of reach of children. Discard any unused portion of the solution.
MabCampath contains no antimicrobial preservative. MabCampath should be used immediately after dilution or within 8 hours if stored at 15 to 30°C. This can only be accepted if preparation of the solution takes place under strict aseptic conditions and the solution is protected from light.