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Drug Details

MabCampath 30mg/ml concentrate for solution for infusion

• Drug Class Description
  Monoclonal antidobies
• Generic Name
  Alemtuzumab
• Presentation
  Concentrate for solution for infusion. Colourless to slightly yellow concentrate.
• Description
  One ml contains 30 mg of alemtuzumab. Each vial contains 30 mg of alemtuzumab. Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for a 21-28 kD lymphocyte cell surface glycoprotein (CD52). The antibody is produced in mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium.
• Indications
  MabCampath is indicated for the treatment of patients with B-cell chronic lymphocytic leukaemia (B-CLL) for whom fludarabine combination chemotherapy is not appropriate.
• Adult Dosage
  

   

   

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

   

  Posology

  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. 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 3-7 days. However, if acute moderate to severe adverse reactions such as hypotension, rigors, fever, shortness of breath, chills, rashes and 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.

  Median duration of treatment was 11.7 weeks for first-line patients and 9.0 weeks for previously treated patients.

  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 (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.

   

  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.

   

  Prophylactic antibiotics

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

   

  Dose modification guidelines

  There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.

  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 interrupted in patients whose platelet count falls to < 25,000/μl or whose absolute neutrophil count (ANC) drops to < 250/μl. MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears. The following table outlines the recommended procedure for dose modification following the occurrence of haematological toxicity while on therapy:

   

  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/or a baseline platelet count  25,000/μl
  For first occurrence	Withhold MabCampath therapy. Resume MabCampath at 30 mg upon return to baseline value(s).
  For second occurrence	Withhold MabCampath therapy. Resume MabCampath at 10 mg upon return to baseline value(s).
  For third occurrence	Discontinue MabCampath therapy.

  *If the delay between dosing is  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)

  Recommendations are as stated above for adults. Patients should be monitored carefully.

   

  Patients with renal or hepatic impairment

  No studies have been conducted.

   

  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 administration

  The MabCampath solution must be prepared according to the instructions. All doses should be administered by intravenous infusion over approximately 2 hours.

   

   

• Child Dosage
  

  The safety and efficacy of MabCampath in children aged less than 17 years of age have not been established. No data are available.

• Elderly Dosage
  

  Recommendations are as stated for adults. Patients should be monitored carefully.

• Contra Indications
  

   hypersensitivity to alemtuzumab, to murine proteins or to any of the excipients;

  - patients with active systemic infections;

  - patients infected with HIV;

  - patients with active second malignancies;

  - pregnancy.

• Special Precautions
  

  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 dose 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 antihypertensive medicinal product. Myocardial infarction and cardiac arrest have been observed in association with MabCampath infusion in this patient population.

  Assessment and ongoing monitoring of cardiac function (e.g. echocardiography, heart rate and body weight) should be considered in patients previously treated with potentially cardiotoxic agents.

  It is recommended that patients be premedicated with oral or intravenous steroids 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 mg, may be given. In the event that acute infusion reactions persist, the infusion time may be extended up to 8 hours from the time of reconstitution of MabCampath in solution for infusion.

  Profound lymphocyte depletion, an expected pharmacological effect of MabCampath, inevitably occurs and may be prolonged. CD4 and CD8 T-cell counts begin to rise from weeks 8-12 during treatment and continue to recover for several months following the discontinuation of treatment. In patients receiving MabCampath as first line therapy, 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/µl. In previously treated patients receiving MabCampath, the median time to reach a level of 200 cells/μl is 2 months following last infusion 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 prophylaxis against Pneumocystis 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/μl or greater, whichever is the later.

  Because of the potential for Transfusion Associated Graft Versus Host Disease (TAGVHD) it is recommended that patients who have been treated with MabCampath receive irradiated blood products.

  Asymptomatic laboratory positive Cytomegalovirus (CMV) viraemia should not necessarily be considered a 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 interrupted until the event resolves. MabCampath treatment may be reinstituted following resolution of the haematological toxicity. 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, loss 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 or chimeric 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.

  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 CLL occurs commonly in this older age group, these patients should be monitored carefully. In the studies in first line and previously treated patients no substantial differences in safety and efficacy related to age were observed; however the sizes of the databases are limited.

• Interactions
  

  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 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 response to any vaccine has not been studied.

• Adverse Drug Reactions
  

  
  

  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.

  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 is 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), cytopenias (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 reactions 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, controlled 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 grouping, undesirable effects observed during treatment or within 30 days following the completion of treatment with MabCampath are presented in order of decreasing seriousness.

   

  System organ class	Very common	Common	Uncommon
  Infections and infestations	Cytomegalovirus viraemia Cytomegalovirus infection	Pneumonia Bronchitis Pharyngitis Oral candidiasis	Sepsis Staphylococcal bacteraemia Tuberculosis Bronchopneumonia Herpes ophthalmicus Beta haemolytic streptococcal infection Candidiasis Genital candidiasis Urinary tract infection Cystitis Body tinea Nasopharyngitis Rhinitis
  Blood and lymphatic system disorder		Febrile neutropenia Neutropenia Leukopenia Thrombocytopenia Anaemia	Agranulocytosis Lymphopenia Lymphadenopathy Epistaxis
  Immune system disorders			Anaphylactic reaction Hypersensitivity
  Metabolism and nutrition disorders		Weight decreased	Tumour lysis syndrome Hyperglycaemia Protein total decreased Anorexia
  Psychiatric disorders		Anxiety
  Nervous system disorders		Syncope Dizziness Tremor Paraesthesia Hypoesthesia Headache	Vertigo
  Eye disorders			Conjunctivitis
  Cardiac disorders		Cyanosis Bradycardia Tachycardia Sinus tachycardia	Cardiac arrest Myocardial infarction Angina pectoris Atrial fibrillation Arrhythmia supraventricular Sinus bradycardia Supraventricular extrasystoles
  Vascular disorders	Hypotension	Hypertension	Orthostatic hypotension Hot flush Flushing
  Respiratory, thoracic and mediastinal disorders		Bronchospasm Dyspnoea	Hypoxia Pleural effusion Dysphonia Rhinorrhoea
  Gastrointestinal disorders	Nausea	Vomiting Abdominal pain	Ileus Oral discomfort Stomach discomfort Diarrhoea
  Skin and subcutaneous tissue disorders	Urticaria Rash	Dermatitis allergic Pruritus Hyperhidrosis Erythema	Rash pruritic Rash macular Rash erythematous Dermatitis
  Musculoskeletal and connective tissue disorders		Myalgia Musculoskeletal pain Back pain	Bone pain Arthralgia Musculoskeletal chest pain Muscle spasms
  Renal and urinary disorders			Urine output decreased Dysuria
  General disorders and administration site conditions	Fever Chills	Fatigue Asthenia	Mucosal inflammation Infusion site erythema Localised oedema Infusion site oedema Malaise

  Acute infusion reactions including fever, chills, nausea, vomiting, hypotension, fatigue, rash, urticaria, dyspnoea, headache, pruritus and diarrhoea have been reported. The majority of these reactions are mild to moderate in severity. Acute infusion reactions usually occur during the first week of therapy and substantially decline thereafter. Grade 3 or 4 infusion reactions are uncommon after the first week of therapy.

   

  Undesirable effects in previously treated patients

  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 grouping, undesirable effects are presented in order of decreasing seriousness.

   

  System organ class	Very common	Common	Uncommon
  Infections and infestations	Sepsis Pneumonia Herpes simplex	Cytomegalovirus infection Pneumocystis jiroveci infection Pneumonitis Fungal infection Candidiasis Herpes zoster Abscess Urinary tract infection Sinusitis Bronchitis Upper respiratory tract infection Pharyngitis Infection	Bacterial infection Viral infection Fungal dermatitis Laryngitis Rhinitis Onychomycosis
  Neoplasms, benign, malignant and unspecified (incl. cysts and polyps)			Lymphoma – like disorder
  Blood and lymphatic system disorder	Granulocytopenia Thrombocytopenia Anaemia	Febrile neutropenia Pancytopenia Leukopenia Lymphopenia Purpura	Aplasia bone marrow Disseminated intravascular coagulation Haemolytic anaemia, Decreased haptoglobin Bone marrow depression Epistaxis Gingival bleeding Haematology test abnormal
  Immune system disorders			Allergic reaction
  			Severe anaphylactic and other hypersensitivity reactions
  Metabolism and nutrition disorders	Anorexia	Hyponatraemia Hypocalcaemia Weight decrease Dehydration Thirst	Hypokalaemia Diabetes mellitus aggravated
  Psychiatric disorders		Confusion Anxiety Depression Somnolence Insomnia	Depersonalisation Personality disorder Abnormal thinking Impotence Nervousness
  Nervous system disorders	Headache	Vertigo Dizziness Tremor Paresthesia Hypoesthesia Hyperkinesia Taste loss	Syncope Abnormal gait Dystonia Hyperesthesia Neuropathy Taste perversion
  Eye disorders		Conjunctivitis	Endophthalmitis
  Ear and labyrinth disorders			Deafness Tinnitus
  Cardiac disorders		Palpitation Tachycardia	Cardiac arrest Myocardial infarction Atrial fibrillation Supraventricular tachycardia Arrhythmia Bradycardia Abnormal ECG
  Vascular disorders	Hypotension	Hypertension Vasospasm Flushing	Peripheral ischaemia
  Respiratory, thoracic and mediastinal disorders	Dyspnoea	Hypoxia Haemoptysis Bronchospasm Coughing	Stridor Throat tightness Pulmonary infiltration Pleural effusion Breath sounds decreased Respiratory disorder
  Gastrointestinal disorders	Vomiting Nausea Diarrhoea	Gastrointestinal haemorrhage Ulcerative stomatitis Stomatitis Abdominal pain Dyspepsia Constipation Flatulence	Gastroenteritis Tongue ulceration Gingivitis Hiccup Eructation Dry mouth
  Hepatobiliary disorders		Hepatic function abnormal
  Skin and subcutaneous tissue disorders	Pruritus Urticaria Rash Hyperhidrosis	Bullous eruption Erythematous rash	Maculo-papular rash Skin disorder
  Musculoskeletal and connective tissue disorders		Arthralgia Myalgia Skeletal pain Back pain	Leg pain Hypertonia
  Renal and urinary disorders			Haematuria Urinary incontinence Urine flow decreased Polyuria Renal function abnormal
  General disorders and administration site conditions	Chills Fever Fatigue	Chest pain Influenza-like symptoms Mucositis Oedema mouth Oedema Asthenia Malaise Temperature change sensation Infusion site reaction Pain	Pulmonary oedema Peripheral oedema Periorbital oedema Mucosal ulceration Infusion site bruising Infusion site dermatitis Infusion site pain

   

  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 arrest, myocardial infarction, arrhythmias, acute cardiac insufficiency and cardiac arrest have been observed. Severe anaphylactic and other hypersensitivity reactions, including anaphylactic shock and angioedema, have been reported following MabCampath administration. These symptoms can be ameliorated or avoided if premedication and dose escalation are utilised.

  Infections and infestations: Serious and sometimes fatal viral (e.g. adenovirus, parainfluenza, hepatitis B, progressive multifocal leukoencephalopathy (PML)), bacterial (including tuberculosis and atypical mycobacterioses, nocardiosis), protozoan (e.g. toxoplasma gondii), and fungal (e.g. rhinocerebral mucormycosis) infections, including those due to reactivation of latent infections have occurred during post-marketing surveillance. The recommended anti-infective prophylaxis treatment appears to be effective in reducing the risk of PCP and herpes infections.

  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: Serious and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, autoimmune thrombocytopenia, aplastic anaemia, Guillain Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy have been reported. A positive Coombs 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.

  Nervous system disorders: Intracranial haemorrhage has occurred with fatal outcome, in patients with thrombocytopenia.

  Cardiac disorders: Congestive heart failure, cardiomyopathy, and decreased ejection fraction have been reported in patients previously treated with potentially cardiotoxic agents.