Consumer medicine information

Mabcampath

Alemtuzumab

BRAND INFORMATION

Brand name

MabCampath

Active ingredient

Alemtuzumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mabcampath.

What is in this leaflet

This leaflet answers some common questions about MabCampath.

It does not contain all the available information. It does not take the place of talking to your Doctor or Pharmacist.

All medicines have risks and benefits. Your Doctor has weighed the risks of you using MabCampath against the benefits they expect it will have for you.

Keep this leaflet with the medicine. You may need to read it again.

What MabCampath is used for

This medicine is an anti-cancer drug used to treat a form of leukaemia known as B cell chronic lymphocytic leukaemia (B-CLL). This is a cancer of the type of white blood cells called lymphocytes.

Patients with B-CLL have too many abnormal lymphocytes, which displace healthy cells in the bone marrow (where most new blood cells are formed) in addition to the blood stream and other organs. Without enough healthy blood cells, infections, anaemia, bruising, excessive bleeding or even organ failure can result.

How it works

MabCampath is a monoclonal antibody that specifically recognises and binds to a unique protein located on the surface of abnormal lymphocytes.

After binding, MabCampath destroys the abnormal lymphocytes, which are then gradually removed from the body by normal biological processes.

Ask your Doctor if you have any questions about why MabCampath has been prescribed for you. Your doctor may have prescribed it for another reason.

There is not enough information to recommend the use of this medicine for children.

There is not enough information to recommend the use of this medicine in patients who have kidney or liver disorders.

Before you are given MabCampath

When you must not be given it

Do not use MabCampath if you have an allergy to:

  • any medicine containing alemtuzumab or murine proteins
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not have treatment with MabCampath if you have any of the following medical conditions:

  • an active infection which is spread around the body
  • HIV
  • an active secondary cancer

Do not have treatment with MabCampath if you are pregnant. It may affect your developing baby if you have it during pregnancy.

Do not breast-feed if you are taking this medicine. Do not begin breast-feeding again until at least 4 weeks after you have finished your treatment and after you have consulted your doctor. It is possible that your baby may be affected if you breast-feed.

If you are not sure whether you should start using this medicine, talk to your Doctor.

Before you are given it

Tell your doctor or pharmacist if you have allergies to any other medicines, or substances such as foods, preservatives or dyes.

Tell your Doctor if you have or have had heart disease, chest pains and/or are receiving treatment to reduce high blood pressure, as MabCampath may make these conditions worse, your doctor will need to monitor you carefully.

Tell your doctor if you have been treated in the past with chemotherapies or general medications that may have a high risk of causing heart damage. Your doctor may wish to monitor your heart function whilst receiving this medicine.

If you have not told your doctor about any of the above, tell him/her before you are given MabCampath.

Taking other medicines

Tell your Doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and MabCampath may interfere with each other. These include:

  • Anti-cancer agents. It is recommended that MabCampath is not given within 3 weeks of other chemotherapeutic agents.
  • Live viral vaccines. It is recommended that patients do not receive live viral vaccines at least 12 months following MabCampath therapy.

There medicines may be affected by MabCampath or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Speak to your doctor before receiving any vaccinations.

Your doctor may have more information on medicines to be careful with or avoid while taking this medicine.

How MabCampath is given

MabCampath is given under the supervision of a specialist doctor experienced in the treatment of your disease.

MabCampath is given in the form of a solution directly in to the blood stream through a vein. This is known as intravenous infusion.

Each time you are given MabCampath, it will take about 2 hours for all the solution to enter your blood.

How much is given and when?

During the first week, 3 mg of MabCampath in the solution is given on Day 1, then 10 mg on Day 2 and then 30 mg on Day 3. MabCampath will continue to be given at 30 mg on each of 3 alternate days each week.

You may experience early side effects and the initial smaller doses may be repeated until the effects go away or reduce. The idea is to increase amounts of MabCampath slowly to reduce the possibility of having side effects and allow your body to tolerate it better.

The doctor will carefully monitor you and decide what are the appropriate amounts of MabCampath to give during your treatment period.

How long is it given?

MabCampath treatment may continue for up to 12 weeks, depending on your progress.

If you receive too much (overdose)

The doctor will treat you as appropriate if you have any ill effects from having been given too much of MabCampath.

In cases of overdose, it is advisable to contact the Poisons Information Centre (Australia: 13 11 26; New Zealand: 0800 POISON or 0800 764 766) for recommendations on the management of overdose.

Symptoms of an overdose may include a severe fever, tiredness, headaches, being short of breath when exercising, dizziness and looking pale.

While you are undergoing treatment with MabCampath

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking MabCampath.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you are a fertile male or female of childbearing potential, ensure that you use reliable form of birth control during treatment and for at least 6 months after treatment. If you do become pregnant while taking this medicine, tell your doctor immediately. The effects of this medicine on reproduction are unknown.

If you are about to have any blood tests, tell all your doctors that you are being treated with this medicine. If may interfere with the results of some tests.

Keep all of your doctor’s appointments so that your progress can be checked. Some side effects (for example, blood disorders) can only be found when your doctor does tests on a regular basis.

If you have pre-existing medical conditions (such as heart disease or chest pains and/or you are receiving treatment to reduce high blood pressure) your doctor will monitor you carefully as MabCampath may make these conditions worse.

Take all medications as prescribed by your doctor. MabCampath causes suppression of the immune system, which affects the natural ability of the body to fight infection for up to six months after treatment. Therefore, you may require antibiotics and antivirals to provide you with extra protection until your immune system has recovered.

Your doctor may also prescribe other additional medication to help alleviate possible side effects.

Things to be careful of

Be careful driving or operating machinery until you know how MabCampath affects you. Confusion and sleepiness have been reported with this medicine.

Side effects

Tell your Doctor as soon as possible if you do not feel well while you are undergoing treatment with MabCampath.

This medicine helps most people with B cell chronic lymphocytic leukaemia (B-CLL), but is may have unwanted side effects. All medicines can have side effects. Sometimes we are serious, most of the time they are not.

The side effects mentioned below are usually due to MabCampath because it affects the body’s immune system in general and reduces resistance to infection. Some infections may be serious and sometimes fatal.

Your doctor may give you other medicines or change your dosage to help reduce any side effects. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your Doctor or Pharmacist to answer any questions you may have.

Tell your doctor if you notice any of them and they worry you:

  • discharge with itching of the eyes and crusty eyelids
  • bleeding or bruising more easily than normal
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale
  • Weight loss, loss of appetite
  • anxiety, confusion, depression, drowsiness, trouble sleeping,unusually overactive
  • fainting, dizziness
  • tremor, pins and needles, decreased feeing or sensitivity, headache, taste loss
  • bluish discoloration of skin, flushing
  • abnormal heart beat (fast or slow)
  • difficulty in breathing, pressure, chest tightness, coughing,
  • nausea, vomiting, stomach pain, diarrhoea, indigestion, constipation, wind
  • rash (itchy or not), excessive sweating, redness of the skin
  • aching muscles, muscle tenderness or weakness (not caused by exercise), back pain, joint pain, chest pain
  • fever, chills, tiredness, unusual weakness
  • feeling of tension or fullness in the nose, cheeks and behind your eyes, sometimes with a throbbing ache, fever, stuffy nose and loss of the sense of smell
  • sore throat and discomfort when swallowing
  • symptoms of low calcium levels in the blood which includes muscle spasm or twitching, numbness or tingling in fingers and toes
  • depression, irritability, confusion, disorientation
  • dehydration or excessive thirst
  • blisters and/or ulcers in the mouth or genitalia
  • symptoms of pneumonia such as fever, chills, shortness of breath, cough and phlegm that may be blood stained
  • flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills
  • burning or pain upon urination, increased frequency to urinate
  • sore, creamy-yellow, raised patches in the mouth
  • itching, burning and a thick, white, “cottage cheese” discharge
  • unexplained weight gain, feeling cold, worsening tiredness, new constipation
  • weight loss, excessive sweating, intolerance to heat, increased bowel movements.

The above list includes the more common side effects of your medicine. They are often mild or moderate problems that are short-lived and diminish during the course of treatment. However, if you believe the side effect is of a more severe nature, tell your doctor as soon as possible.

Tell your doctor immediately if you notice any of the following:

  • vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
  • unusually swollen glands in the neck, armpit or groin
  • loss of hearing
  • loss of control of your bladder or bowels

The above list includes serious side effects that may require medical attention.

Serious side effects are usually uncommon or rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • signs of heart attack such as central crushing chest pain, aching sensation in your chest or arms that may spread to your neck, jaw or back, pain in left arm, increased sweating
  • signs of a stroke such as drooping of the skin on your face or sudden weakness or numbness on one side of the body or sudden difficulty with speech or your vision
  • signs of tumour lysis syndrome such as pain in one side of the body under the rib cage, little or no urine, drowsiness, nausea, vomiting, breathlessness, irregular heart beat, loss of memory, loss of consciousness
  • Signs of haemophagocytic lymphohistiocytosis (excessive activation of white blood cells) such as fever, swollen glands, bruising, or skin rash. Haemophagocytic lymphohistiocytosis can be fatal if not diagnosed and treated early
  • Signs of glomerulonephritis such as pink or cola-colored urine, or foam in the urine, or noticeable swelling face, hands, feet and abdomen.
  • signs of Guillain-Barre syndrome, which is a temporary inflammation of the nerves, causing pain, weakness, and paralysis in the extremities and often progressing up to the chest and face
  • abnormally fast or irregular heart beat
  • extreme difficulty breathing, shortness of breath, sharp chest pains which are worse when breathing in, frequent fainting
  • severe bleeding or bruising more than usual (e.g. persistent nose bleeds)
  • signs of intracranial haemorrhage such as severe headache, nausea and vomiting, alertness changes, problems with speech, balance, coordination or focusing the eyes

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are usually uncommon or rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Keep all doctors appointments so your progress can be checked. Some side effects (for example, blood disorders) can only be found when your doctor does tests on a regular basis.

After using MabCampath

Storage

MabCampath will be stored by your doctor. Storage conditions are outlined below for your information.

MabCampath vials: Store at 2-8°C (in a refrigerator). Do not freeze. Protect from light.

MabCampath reconstituted solution:

Should be used immediately after dilution or within 8 hours after dilution. Solutions may be stored at 15-300C 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.

MabCampath contains no antimicrobial preservative.

Product description

What it looks like

MabCampath is diluted for administration via intravenous drip.

Each pack of MabCampath contains three 2 mL clear glass vials. Each vial contains 1 mL colourless to slightly yellow concentrate.

Ingredients

Each MabCampath vial contains 30 mg of alemtuzumab as the active ingredient which is equivalent to 1 mL of a 30 mg/mL solution.

It also contains:

  • disodium edentate
  • phosphate buffered saline. This consists of polysorbate 80, potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate and water for injections to make up 1mL

Sponsor

MabCampath is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Freecall No: 1800 818 806

In New Zealand this product is distributed by:

sanofi-aventis new zealand limited
Level 8, James and Wells Tower
56 Cawley Street, Ellerslie,
Auckland
New Zealand
Freecall No:0800 283 684

Australian Registration Numbers:

AUST R 116622

mabcampath-ccdsv18-cmiv3-10jan20

This leaflet was prepared in January 2020

Published by MIMS March 2020

BRAND INFORMATION

Brand name

MabCampath

Active ingredient

Alemtuzumab

Schedule

S4

 

1 Name of Medicine

Alemtuzumab (rch).

6.7 Physicochemical Properties

The alemtuzumab molecule consists of two ~ 24 kD small polypeptide chains (light chains, 214 amino acids) and two larger ~ 49 kD polypeptide chains (heavy chains, 450 amino acids) linked together by two inter (light chain - heavy chain) disulphide bridges and two inter (heavy chain - heavy chain) disulphide bridges to form a Y-shaped molecule, typical for immunoglobulins of the IgG1 subclass.
Each molecule also contains a total of 12 intrachain disulphide bridges and an asparagine residue (301) in each heavy chain which is glycosylated.

Chemical structure.

The structure is provided below:

CAS number.

Not applicable.

2 Qualitative and Quantitative Composition

Each vial contains 30 mg/mL alemtuzumab as a concentrated solution for infusion. See Section 6.1 List of Excipients.

3 Pharmaceutical Form

Alemtuzumab (rch) is a recombinant DNA-derived humanized monoclonal antibody directed against the 21-28 kD cell surface glycoprotein, CD52. Alemtuzumab (rch) is an IgG1 kappa antibody with human variable framework and constant regions, and complementarity-determining regions from a murine monoclonal antibody. The antibody has an approximate molecular weight of 150 kD. Alemtuzumab (rch) is produced in mammalian cell (Chinese hamster ovary) suspension culture in a nutrient medium.
Alemtuzumab (rch) is a sterile, clear, colourless to slightly yellow, injection concentrate. It is intended for dilution prior to infusion.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Alemtuzumab is a genetically engineered humanised IgG1 kappa monoclonal antibody specific for a 21-28 kD lymphocyte cell surface glycoprotein (CD52) antigen. It was generated by the insertion of six complementary determining regions from an IgG2a rat monoclonal antibody into a human IgG1 immunoglobulin molecule.
Alemtuzumab causes the lysis of lymphocytes by binding to CD52 antigen, which is expressed on the surface of essentially all B and T lymphocytes (benign and malignant) as well as monocytes, thymocytes and macrophages, sperm and epithelial cells of epididymis and seminal vesicle. 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.

Clinical trials.

Previously treated B-CLL patients.

Determination of the efficacy of MabCampath is based on overall response and survival rates. Data available from three uncontrolled B-CLL studies are summarised in the Table 4.

First line B-CLL patients.

The safety and efficacy of MabCampath were evaluated in a phase 3, open label, randomised 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).
The secondary objectives included complete response (CR) and overall response (CR or partial response (PR)) rates using the 1996 NCIWG criteria, the duration of response, time to alternative treatment and safety of the two treatment arms. See Table 5.
There are no data on the safety and efficacy of retreatment with alemtuzumab in patients who received the drug as first line therapy.

Cytogenetic analyses in first line B-CLL patients.

The cytogenetic profile of B-CLL has been increasingly recognised as providing important prognostic information and may predict response to certain therapies. Of the first line patients (n = 282) in whom baseline cytogenetic (FISH) data were available in study 4, chromosomal aberrations were detected in 82%, while normal karyotype was detected 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.
Overall response rate (ORR) was superior in patients 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). Complete remissions 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 in patients with 17p deletion, trisomy 12 and normal karyotype, which did not reach significance due to small sample size.

Assessment of cytomegalovirus (CMV) by PCR.

In the randomised 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 CMV infection during treatment with MabCampath had no measurable impact on progression free survival (PFS).

5.2 Pharmacokinetic Properties

Pharmacokinetics were characterised in alemtuzumab naive patients with B cell chronic lymphocytic leukaemia (B-CLL) who had failed previous therapy with purine analogues. Alemtuzumab was administered as a 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. Alemtuzumab pharmacokinetics followed a 2 compartment model and displayed nonlinear 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 decreased with repeated administration due to decreased receptor mediated clearance (i.e. loss of 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 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

Genotoxicity.

No in vitro or animal studies have been conducted with MabCampath to assess the mutagenic potential.

Carcinogenicity.

No in vitro or animal studies have been conducted with MabCampath to assess the carcinogenic potential.

4 Clinical Particulars

4.1 Therapeutic Indications

MabCampath is indicated for the treatment of patients with B cell chronic lymphocytic leukaemia (B - CLL).

4.3 Contraindications

MabCampath is contraindicated in:
Hypersensitivity or anaphylactic reactions to alemtuzumab, to murine proteins or to any of the excipients;
In patients with active systemic infections;
In patients infected with HIV;
In patients with active secondary malignancies;
Pregnancy;
Breast-feeding.

4.4 Special Warnings and Precautions for Use

Infusion related reactions.

MabCampath can result in serious and, in some instances, fatal, infusion reactions. Patients should be carefully monitored during infusions and MabCampath discontinued if indicated. Gradual escalation to the recommended maintenance dose is required at the initiation of therapy and after interruption of therapy for 7 or more days (see Section 4.2 Dose and Method of Administration).
Patients may have allergic or hypersensitivity reactions to MabCampath and to murine or chimeric monoclonal antibodies (see Section 4.3 Contraindications). If any of these occur medications for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures is necessary.
Acute adverse reactions, which may occur during initial dose escalation 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 acute infusion related 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. Grade 3 or 4 (according to Common Terminology Criteria for Adverse Events-CTCAE) infusion related reactions are uncommon after the first week of therapy.
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.
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.
Transient hypotension has occurred in patients receiving MabCampath. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischaemic heart disease, angina and/or in patients receiving antihypertensive medication. 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.
Therapy should be discontinued if there is evidence of disease progression (see Section 4.2 Dose and Method of Administration).

Immunosuppression.

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 median time to recovery of CD4+ counts to ≥ 200 cells/microL occurred by 6 months post-treatment, however, at 2 months post-treatment the median was 183 cells/microL. In previously treated patients receiving MabCampath, the median time to reach a level of 200 cells/microL 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.
Serious, sometimes fatal bacterial, viral, fungal and protozoan infections have been reported in patients receiving MabCampath therapy. Prophylaxis directed against Pneumocystis jirovecii pneumonia and herpes virus infections has been shown to decrease, but not to eliminate, the occurrence of these 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 jirovecii pneumonia (PCP) and an effective oral antiherpes agent, such as famciclovir 500 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/microL or greater, whichever is the later.
Because of the potential of transfusion associated graft versus host disease (TAGVHD), it is recommended that patients who have been treated with MabCampath should receive irradiated blood products.
Asymptomatic laboratory positive cytomegalovirus (CMV) 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.

Haemophagocytic lymphohistiocytosis (HLH).

During post-marketing use, HLH has been reported in patients treated with MabCampath. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Symptoms have been reported to occur within a few months following the initiation of treatment, commonly observed in association with infections. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered.

Haematological toxicity.

Serious and in rare instances fatal, pancytopenia, autoimmune idiopathic thrombocytopenia and autoimmune haemolytic anaemia have occurred in patients receiving MabCampath. Single doses of MabCampath greater than 30 mg or cumulative doses greater than 90 mg per week should not be administered because these doses are associated with a higher incidence of pancytopenia.
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 (see Section 4.2 Dose and Method of Administration). 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.

CD52 expression.

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 patients in both treatment arms of the first line study, loss of CD52 expression was not observed around the time of progression or death.

Use in hepatic impairment.

No studies have been conducted in patients with hepatic impairment.

Use in renal impairment.

No studies have been conducted in patients with renal impairment.

Use in the elderly

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 (see Section 4.2 Dose and Method of Administration). 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.

Paediatric use.

No studies have been conducted to investigate the safety and efficacy of MabCampath in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The potential effects on fertility have not been investigated in animal studies. CD52 is expressed on sperm and epithelial cells of the epididymis and seminal vesicle. It is not known whether MabCampath can affect the reproductive capacity of men or women.
(Category B2)
MabCampath is contraindicated during pregnancy. Human IgG is known to cross the placental barrier; MabCampath is likely to 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.
Males and females of childbearing potential should use effective contraceptive measures during treatment and for 6 months following MabCampath therapy (see Section 4.6 Fertility, Pregnancy and Lactation).
MabCampath is contraindicated during breastfeeding. It is not known whether MabCampath is excreted in human milk. Breastfeeding should be discontinued during treatment and for at least 4 weeks following MabCampath therapy. No studies have been performed in lactating animals.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).
The frequencies of the adverse reactions by system organ classes and in descending order of severity in Tables 2 and 3, are based on clinical trial data.

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.

Undesirable effects in first line patients.

Safety data in first line - B-CLL patients are based on 147 patients enrolled in a randomised, 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 during the first week of therapy.
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
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 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 3.0) infusion reactions are uncommon after the first week of therapy.

Post marketing data.

The reactions presented in this section were identified mainly from post marketing experience in previously treated patients. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to MabCampath exposure. Decisions to include these reactions in labelling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to MabCampath. Events previously identified in clinical studies are not listed in this section.

Blood and lymphatic system disorders.

Severe bleeding reactions have been reported.

Cardiac disorders.

Cardiomyopathy, congestive heart failure and decreased ejection fraction have been reported in patients previously treated with potentially cardiotoxic agents.

Immune system disorders.

Serious and sometimes fatal autoimmune phenomena including autoimmune haemolytic anaemia, autoimmune thrombocytopenia, aplastic anaemia, Graves' disease, Guillian-Barré syndrome and its chronic form, chronic inflammatory demyelinating polyradiculoneuropathy, serum sickness have been reported. A positive Coombs' test has also been observed. Fatal transfusion associated graft versus host disease has also been reported. Haemophagocytic lymphohistiocytosis (HLH).

Infusion reactions.

Serious and sometimes fatal reactions including bronchospasm, hypoxia, syncope, pulmonary infiltrates, 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 (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Infections and infestations.

Serious and sometimes fatal viral (e.g. adenovirus, parainfluenza, hepatitis B, progressive multifocal leukoencephalopathy [PML], bacterial (including tuberculosis and atypical mycobacteriosis, nocardiosis), protozoan (e.g. Toxoplasma gondii) and fungal (e.g. rhinocerebral mucormycosis) infections, including those due to reactivation of latent infections, have been observed during post marketing surveillance. The recommended anti-infective prophylaxis appears to be effective in reducing the risk of Pneumocystis jirovecii pneumonia (PCP) and herpes infections (see Section 4.4 Special Warnings and Precautions for Use). Epstein Barr virus (EBV)-associated lymphoproliferative disorder has been reported.

Metabolism and nutrition disorders.

Tumour lysis syndrome with fatal outcome has been reported.

Nervous system disorders.

Intracranial haemorrhage has occurred with fatal outcome in patients with thrombocytopenia. Stroke, including haemorrhagic and ischaemic stroke.

Renal and urinary disorders.

Glomerulonephritis.

Post marketing experience with Lemtrada.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to alemtuzumab exposure.
The following adverse reactions were identified during post-approval use of alemtuzumab for the treatment of relapsing forms of multiple sclerosis (MS):

Nervous system disorders.

Stroke, including haemorrhagic and ischaemic stroke and cervicocephalic arterial dissection.

Endocrine disorders.

Hypothyroidism, hyperthyroidism, and thyroiditis.

4.2 Dose and Method of Administration

General considerations.

MabCampath should be administered under the supervision of a physician experienced in the use of cancer therapy.
Medications for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures is necessary.
MabCampath solution must be prepared according to the instructions provided under 'Instructions for use and handling and disposal'. All doses should be administered by intravenous infusion over approximately 2 hours.
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 Section 4.4 Special Warnings and Precautions for Use).
Antibiotics and antivirals should be administered routinely to all patients throughout and following treatment (see Section 4.4 Special Warnings and Precautions for Use).

Dose.

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 due to cytokine release (hypotension, rigors, fever, shortness of breath, chills, rashes 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 before further dose escalation is attempted (see Section 4.4 Special Warnings and Precautions for Use).
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.
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/microL or whose absolute neutrophil count (ANC) drops to < 250/microL. MabCampath may be reinstituted after the infection or toxicity has resolved. MabCampath should be permanently discontinued if autoimmune anaemia or autoimmune thrombocytopenia appears. Table 1 outlines the recommended procedure for dose modification following the occurrence of haematological toxicity while on therapy.
There are no dose modifications recommended for severe lymphopenia given the mechanism of action of MabCampath.

Instructions for reconstitution, handling and disposal.

The vial contents should be inspected for particulate matter and discolouration prior to administration. If particulate matter is present or the concentrate is coloured, then the vial must 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 within 8 hours after preparation. The required amount of the vial contents should be added 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 those mentioned above.
There are no known incompatibilities with other medicinal products. However, other medicinal products should not be added to the MabCampath infusion solution or simultaneously infused though the same intravenous line.
Women who are pregnant or planning pregnancy should not handle MabCampath.
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 vial or other accidental spillage.
Procedures for proper handling and disposal should be observed. Any spillage or waste material should be disposed of by incineration.

Patients with renal impairment.

No studies have been conducted in patients with renal impairment.

Patients with hepatic impairment.

No studies have been conducted in patients with hepatic impairment.

Elderly patients (over 65 years of age).

Recommendations are as stated above for adults. Patients should be monitored carefully (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, caution should be exercised as confusion and somnolence have been reported.

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.
For general advice on overdose management, contact the Poisons Information Centre, telephone number 13 11 26 (Australia) or the National Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

0.0187 mg disodium edetate, 0.1 mg polysorbate 80, 0.2 mg potassium chloride, 0.2 mg monobasic potassium phosphate, 8 mg sodium chloride, 1.15 mg dibasic sodium phosphate heptahydrate, and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

MabCampath vials should be stored at 2 - 8°C (in a refrigerator).
Do not freeze. Protect from light.

Reconstituted solution.

MabCampath contains no antimicrobial preservative. To reduce microbiological hazard, use as soon as practicable after reconstitution/ preparation. If storage is necessary, hold at 2°C to 8°C for not more than 8 hours. This can only be accepted if preparation of the solution takes place under strictly aseptic conditions and the solution is protected from light.

6.5 Nature and Contents of Container

Vials of 2 mL, clear, glass type I, containing 1 mL colourless to slightly yellow concentrate.
Pack size: 3 vials.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes