MabCampath - summary of medicine characteristics

not appropriate

day 1, 10 mg on da

of action

should be interrupted ted in patients whose rops to < 250/pl.

. MabCampath should be cytopenia appears. The

ication following the occurrence

It is recommended that patients be premedicated with oral or intrave prior to each MabCampath infusion during dose escalation and as be discontinued as appropriate, once dose escalation has been achie

roids 30 – 60 minutes indicated. Steroids may addition, an oral

antihistamine, e.g. diphenhydramine 50 mg, and an analgesic, eracetamol 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 pharm      ical 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 sev nths following the discontinuation of treatment. In patients receiving MabCampath as first apy, the recovery of CD4+ counts to >200 cells/^l occurred by 6 months post-treatment, h r, at 2 months post-treatment the median was 183

cells/pl. In previously treated cells/pl is 2 months following approximate pretreatment leve recommended that anti-infecti

3 times weekly, or other pro oral anti-herpes agent, such

, the median time to reach a level of 200 but may take more than 12 months to to opportunistic infections. It is highly prophylaxis (e.g. trimethoprim/sul­famethoxazole 1 tablet twice daily, axis against Pneumocystis jiroveci pneumonia (PCP) and an effective

and for a mini CD4+ count h

as famciclovir, 250 mg twice daily) should be initiated while on therapy

onths following completion of treatment with MabCampath or until the d to 200 cells/pl or greater, whichever is the later.

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.

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, los 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 o 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 contrac treatment and for 6 months following MabCampath therapy (see sections

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). 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.

Although no formal drug interaction stu known clinically significant int MabCampath is a recombinant be expected. However, it is rec other chemotherapeu­tic agents

e been performed with MabCampath, there are no abCampath with other medicinal products. Because otein, a P450 mediated drug-drug interaction would not t MabCampath should not be given within 3 weeks of

Although it has not be in, at least, the 12 anamnestic h

4.6 Fert

d, it is recommended that patients should not receive live viral vaccines wing MabCampath therapy. The ability to generate a primary or nse to any vaccine has not been studied.

abCampath is contraindicated during pregnancy. Human IgG is known to cross the placental barrier; abCampath may cross the placental barrier as well and thus potentially cause foetal B and T cell ymphocyte depletion. Animal reproduction studies have not been conducted with MabCampath. It is ot 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.

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 been performed. However, caution should be exercised as confusion and somnolence have been reported.

The tables below report adverse reactions by MedDRA system organ classes (MedDRA frequencies are based on clinical trial data.

The most appropriate MedDRA term is used to describe a certain reaction and its syn 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 (<1/10,0 infor­mation is available for events that occur at lower frequency, due to the size of the ion studied; n=147 for first line treated patients and n=149 for previously treated patients.

ns (pyrexia, chills, ias (neutropenia, lymphopenia, infection, other infections),

The most frequent adverse reactions with MabCampath are: in hypotension, urticaria, nausea, rash, tachycardia, dyspnoea), thrombocytopenia, anaemia), infections (CMV viraemia, C gastrointestinal symptoms (nausea, emesis, abdominal pain), and neurological symptoms (insomnia, anxiety). The most frequent serious adverse reactiocytopenias, infusion reactions, and immunosuppres­sion/infection­s.

Undesirable e ffects 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 l

Within each freque

nts usually occurred in the first week of therapy.

ping, undesirable effects observed during treatment or within 30 days

following the completion of treatment with MabCampath are presented in order of decreasing seriousness.

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, h pulmonary infiltrates, acute respiratory distress syndrome (ARDS), respiratory arr infarction, arrhythmias, acute cardiac insufficiency and cardiac arrest have been o

anaphylactic and other hypersensitivity reactions, including anaphylactic sh been reported following MabCampath administration. These symptoms can if premedication and dose escalation are utilised (see section 4.4).

eliorated or avoided

yncope, ardial

d. Severe gioedema, have

Infections and infestations: Serious and sometimes fatal viral (e. B, progressive multifocal leukoencephalopathy (PML)), bacteri

mycobacterioses, nocardiosis), protozoan (e.g. toxoplasma mucormycosis) infections, including those due to reactivati post-marketing surveillance. The recommended anti-infecti

irus, parainfluenza, hepatitis g tuberculosis and atypical d fungal (e.g. rhinocerebral

effective in reducing the risk of PCP and herpes infections (see section 4.4).

of latent infections have occurred during prophylaxis treatment appears to be

EBV-associated lymphoproliferative disorders, in some cases fatal, have been reported.

Blood and lymphatic system disorders:

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 GVHD) has also been reported.

Metabolism

al disorders: Tumour lysis syndrome with fatal outcome has been reported.

Nervous sy thrombocyt

¡orders: Intracranial haemorrhage has occurred with fatal outcome, in patients with

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

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.

75

50

Estimated Probability 100

Figure 1: Progression free survival in first line study (by treatment group)

Stratified log-rank test: p=0 0001

32

'd Ratio: 0.58

2I: 0.43, 0.77

28

83

122

110

4

5

th V lorambucil 148

el, randomized tients requiring therapy ured by the primary

36    40

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 available from three uncontrolled B-CLL studies are summarised in the following table:

= not reache

5.2

acokinetics were characterised in MabCampath-naive patients with B-cell chronic lymphocytic mia (B-CLL) who had failed previous therapy with purine analogues. MabCampath was istered as a 2 hour intravenous infusion, at the recommended dosing schedule, starting at 3 mg

increasing to 30 mg, 3 times weekly, for up to 12 weeks. MabCampath pharmacokinetics followed

a 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 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

Campath to assess carcinogenic

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.

Clear Type I glass ampoule, containing 3 ml of concentrate. Pack size: carton of 3 ampoules.

The ampoule contents should be inspected for particulate matter and discolouratio 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 rec should be prepared for intravenous infusion using aseptic techniques and infusion should be administered within 8 hours after preparation

required amount of the ampoule contents should be added, via 5 ^m filter, to 100 ml of sodium chloride 9 mg/ml (0.9%) so solution for infusion. The bag should be inverted gently ensure the sterility of the prepared solution particularly as i

ed that MabCampath diluted solution for ted from light. The -protein binding, non-fibre

r infusion or glucose (5%) solution. Care should be taken to ntains no antimicrobial preservatives.

Other medicinal products should not be added to infused through the same intravenous line (see section 4.5).

infusion solution or simultaneously

Caution should be exercised in the handli latex gloves and safety glasses is rec or other accidental spillage. W MabCampath.

preparation of the MabCampath solution. The use of ended to avoid exposure in case of breakage of the ampoule are pregnant or trying to become pregnant should not handle

Procedures for proper handling isposal should be observed. Any spillage or waste material should be disposed of by incineration.

7. MAR

Genzy Gooi

aarden

V

EU/1/01/193/001

Date of first authorisation: 06/07/2001

Date of latest renewal: 10/07/2011