Summary Basis of Decision for Treanda ®

The Canadian regulatory decision on the clinical pharmacology, efficacy, and safety of Treanda was based on a critical assessment of the Canadian application/submission. As an added reference, Health Canada consulted the review reports from the United States FDA under the provisions of Method 3 of the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

3.3.1 Pharmacodynamics

The cytotoxic activity of bendamustine HCl was evaluated against a range of human solid tumour and leukaemic cell lines. In the tumour cell lines tested, bendamustine HCl showed a wide range of IC₅₀ values. The greatest potency was observed for the two SCLC lines NCI-H69 (IC₅₀ = 4 µM) and NCI-H146 (IC₅₀ = 6 µM). Inhibitory concentration values at or below 20 µM were also determined for the T47D and MDA-MB-453 breast cancer cell lines, the CCRF-SB-cell ALL cell line, the KG-1 AML cell line, and the Namalwa NHL cell line.

In xenograft models of lymphoma, bendamustine HCl treatment inhibited tumour growth. Bendamustine HCl also demonstrated activity in xenograft models of human lung and breast cancers.

In NHL patients, bendamustine HCl exposure [AUC_0-∞ and maximum concentration (C_max)] was not influenced by the covariates analyzed [age, sex, weight, et cetera (etc.)] and was not a significant predictor of responder status, duration of response or progression-free survival. The pharmacokinetic/pharmacodynamic analyses were also unable to establish a relationship between exposure and treatment emergent adverse events with the exception of nausea. There was a positive correlation between nausea and bendamustine HCl C_max but not AUC_0-∞.

3.3.2 Pharmacokinetics

Absorption

The maximum bendamustine HCl plasma concentration (C_max) typically occurred at the end of the 30 or 60 minute IV infusion. A decline from peak bendamustine HCl plasma concentration occurred in a triphasic manner characterized by rapid distribution and intermediate phases followed by a slower terminal phase. The majority of the AUC was accounted for by the initial two phases, with the terminal portion of the curve representing less than 1% of the overall exposure.

Distribution

A human mass balance study found that bendamustine HCl has limited tissue distribution and is detected at highest concentrations in the liver and kidney shortly after injection. Bendamustine HCl was also found in the gallbladder, related to the biliary elimination of bendamustine HCl and/or its metabolites. Conversely, brain levels of bendamustine HCl were low which suggests poor transport across the blood-brain barrier.

Peak plasma concentrations of bendamustine HCl following a single IV administration were achieved at the end of the one-hour infusion in NHL patients. Bendamustine HCl has a mean steady state volume distribution (V_ss) of approximately 20 L.

Metabolism

Consistent with the in vitro data (see section 3.3.2 Pharmacokinetics) the concentration of the two CYP1A2 active metabolites, M3 and M4, are detected in human plasma at 9% and 1% the levels of the parent compound (based on AUC), respectively. This suggests cytotoxic activity is primarily due to bendamustine HCl.

Excretion

Following IV administration of radiolabelled bendamustine HCl, mean recovery was 76% of the total radioactivity administered to cancer patients when collected up to day 8 (168 hours post-dose). Approximately half (45.5% of the dose) was excreted in the urine and approximately one quarter (25.2% of the dose) was recovered in the faeces. It is not clear if the 24% unaccounted for radioactivity reflects greater retention of bendamustine derived species in humans compared to rats or if it was lost during processing of samples.

Bendamustine HCl clearance is approximately 700 mL/minute. Following a single IV dose of 120 mg/m² bendamustine HCl over 1 hour, the mean apparent terminal elimination half-life (t_1/2) of bendamustine HCl is approximately 40 minutes. The mean apparent t_1/2 of the two active metabolites M3 and M4 are approximately 3 hours and 40 minutes, respectively.

Drug Interactions

There is a potential for CYP1A2 inhibitors [for example (e.g.) fluvoxamine, ciprofloxacin] or inducers (e.g., omeprazole, smoking) to affect the circulating levels of bendamustine and its active metabolites. However, it is unknown if this will significantly impact the activity of bendamustine in patients. Caution should be used, or alternative treatments considered, if concomitant treatment with CYP1A2 inhibitors or inducers is needed.

3.3.3 Clinical Efficacy

Non-Hodgkin's Lymphoma (Indolent Disease)

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of over forty lymphoproliferative malignancies with diverse patterns of behaviours and responses to treatments. The NHLs can be divided into aggressive and indolent types. Treatment options available for patients with indolent NHL induce substantial responses; however there is no curative regimen and patients usually relapse. Hence, patients require multiple chemotherapy regimens throughout the course of their disease.

The clinical efficacy of Treanda in the treatment of relapsed indolent NHL was evaluated in a single-arm, multicentre, pivotal study (Study SDX-105-03) of patients who had prior chemotherapy and did not respond to or progressed within 6 months of a rituximab-based regimen. Patients received Treanda intravenously at a dose of 120 mg/m² on Days 1 and 2 of a 21-day treatment cycle. Treatment was planned for a minimum of 6 cycles. If patients were still receiving clinical benefit after 6 cycles of treatment, they could continue treatment for a maximum of 8 cycles. The median number of cycles received was 6 and the mean relative dose intensity was 88%. Eighty-four percent (84%) of patients were considered asymptomatic at the time of treatment. There was concern during the review that these patients may not need immediate treatment. This concern was addressed noting that the definition used to define asymptomatic in the study was quite narrow and that other recorded clinical features indicated a need for these patients to be treated. Furthermore, all patients except one had previous chemotherapy. In considering this, the patient population would be similar to North American patients who would be treated with Treanda as a monotherapy.

The study was conducted by 28 investigators at 24 centres in the United States and 4 centres in Canada. In addition to prior rituximab treatment, patients were required to have received at least one prior chemotherapy regimen, with a maximum of three prior chemotherapy regimens.

One hundred and two patients (102) were enrolled and 100 patients were treated with Treanda. The mean age of the enrolled patients was 59.3 years, 65% were male, and 95% of the patients had a baseline World Health Organization (WHO) performance status of 0 or 1. Patients with a performance status of 0 are considered to be fully active and able to perform day to day tasks in the same manner as before they were ill. Patients with a performance status of 1 are unable to carry out heavy physical work, but can do essentially anything else. Of the patients treated with Treanda, the major tumour subtypes included in the study were follicular lymphoma (FL) (62%), diffuse small lymphocytic lymphoma (SLL) (21%), and marginal zone lymphoma (16%). Patients with SLL were eligible for this study and the chronic lymphocytic leukaemia (CLL) pivotal study (see below). Ninety-nine percent (99%) of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or the last dose (maintenance regimen or combination therapy) of rituximab.

Efficacy was based on the assessments by a blinded independent review committee (IRC) and included Overall Response Rate [ORR - percentage of patients with a complete response (CR) + complete response unconfirmed (CRu) + partial response (PR)] and Duration of Response (DR). The study was designed to rule out an ORR of <40% and a duration of response of <4 months (null hypothesis). Tumour assessments were performed every 6 weeks for the first two tumour assessments and every 12 weeks thereafter until the patient completed treatment.

The effectiveness of Treanda was assessed using the primary objectives of ORR and DR in patients. Patients had an ORR of 75% [95% Confidence Interval (CI): 65.3, 83.1]. There were 58% of patients with a PR, 14% with a CR, and 3% with a CRu. Responses were seen in patients who previously received another alkylating agent (ORR- 74%), patients with disease refractory to prior alkylating agent therapy (ORR - 60%), patients with disease refractory to their last chemotherapy (ORR - 64%), and patients with prior radioimmunotherapy (ORR - 63%).

Durable responses were seen across all patient groups defined by baseline characteristics. The median DR reported was 40 weeks (95% CI: 31.0, 46.9). Timing of the tumour measurements and off-schedule assessments were concerns raised by Health Canada that may have artificially inflated the DR. Sensitivity analyses were requested from the sponsor and the additional analyses provided supported the primary analysis. The large percentage of patients who responded and the duration of the response are considered beneficial for an indolent NHL patient population requiring treatment and who have limited treatment options available.

Overall, this pivotal study shows promising anti-tumour activity in patients with indolent forms of NHL, most commonly FL and SLL. An ORR of 75% (mainly PRs) is significant for a patient population that is not only refractory to rituximab but for whom the majority have been treated with prior alkylating agents. The DR of 30-40 weeks is an important component of the primary efficacy analysis. Despite this efficacy, serious side effects have been reported with Treanda. There were 11 deaths during this study and 6 were considered either possibly (2), probably (2) or definitely (2) related to bendamustine HCl by either the investigator or Cephalon medical advisor.

Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia, the most common adult leukaemia in the Western hemisphere, is a chronic lymphoproliferative disorder characterized by a progressive accumulation of functionally abnormal B-lymphocytes of monoclonal origin within the blood. The disease initially follows an indolent course, and the recommended approach for patients in early stages with no specific risk factors or evidence of progression is watchful waiting. Treatment is initiated for patients with symptomatic disease (e.g., painful lymphadenopathy, fatigue, unexplained weight loss, fever, or night sweats) and for those patients with evidence of rapidly progressive disease (lymphocytosis; rapid enlargement of lymph nodes, liver, or spleen; anaemia or thrombocytopaenia).

The clinical efficacy of Treanda in the treatment of CLL was evaluated in a single open-label, 1:1 randomized, controlled multicentre, Phase III study comparing Treanda to the alkylating agent chlorambucil (Study 02CLLIII). The study was conducted in 319 previously untreated CLL patients with Binet Stage B or C (Rai Stages I - IV) requiring treatment. The Binet staging system classifies CLL according to the number of lymphoid tissues that are involved as well as the presence of anaemia or thrombocytopaenia. Stage A is the least severe. The Rai staging system classifies CLL into low, intermediate and high-risk categories with 0 being the lowest risk and IV being the highest risk.

All patients met the need-to-treat (i.e., symptomatic) criteria defined as 1 of the following: haematopoietic insufficiency with non-haemolysis-induced haemoglobin of less than 10 g/dL; thrombocytopaenia of less than 100 x 10⁹ platelets/L; B symptoms defined as an unexplained weight loss of more than 10% in the last 6 months, a persistent or recurrent fever of unknown origin of more than 38ºC, and night sweats; rapidly progressive disease (such as rapid lymphoma growth, rapid increase in lymphocyte count, rapid fall in haemoglobin or platelet count not due to autoimmune phenomena); risk of organ complications from bulky lymphomas (e.g., vascular compression). Patients with autoimmune haemolytic anaemia or autoimmune thrombocytopaenia, Richter’s syndrome, or transformation to prolymphocytic leukaemia were excluded from the study.

The randomized study was conducted at 45 centres in 8 countries. The majority of patients were enrolled in study centres in Germany (40%) and Bulgaria (37%). The 6 countries accounting for the remaining 23% of study patients were Italy (10%), Spain (6%), France (5%), Sweden (1%), Austria (1%), and England (<1%).

The patient populations in the Treanda and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age; gender; Binet stage [72% versus (vs.) 71% Binet B]; lymphadenopathy (79% vs. 80%); enlarged spleen (77% vs. 78%); enlarged liver (49% vs. 45%); hypercellular bone marrow (80% vs. 72%); B-symptoms (50% vs. 50%); lymphocyte count (mean 69.3 x⁹/L vs. 63.2 x⁹/L); and serum lactate dehydrogenase (LDH) concentration (mean 369.4 U/L vs. 385.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19, CD20 or both).

Patients were randomly assigned 1:1 to treatment with Treanda or chlorambucil stratified by study centre and Binet stage (B or C). Patients received either Treanda at 100 mg/m², administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg [Broca’s normal weight (height in cm -100 to give weight in kg)] administered orally on Days 1 and 15 of each 28-day cycle.

The two primary endpoints of this study were overall response rate (ORR) and progression-free survival (PFS). Important secondary endpoints were overall survival (OS) and quality of life (QoL).

As a result of the open-label nature of the study and potential concerns of bias, an Independent Committee for Response Assessment (ICRA) was established during the conduct of the study to ensure that the response evaluations were consistently managed. The ICRA performed a blinded review based on assessments conducted every 12 weeks and determined a best overall response for each patient and a date of progression when indicated.

A calculated response analysis based on the ICRA adjudicated data is reported as the final efficacy measures for ORR and PFS. In this analysis, the National Cancer Institute-sponsored Working Group (NCI-WG) criteria were applied programmatically to the data using the variables of lymph node measurements, records of B-symptoms, haematology laboratory data, and records of transfusions and new anticancer treatments. In the calculated response analysis, patients were censored if they had a transfusion or started a new anticancer treatment before documented progression. Patients were also required to have a confirmed normocellular bone marrow within 56 days of the initial clinical assessment to be classified as having a CR. Patients who met all other requirements for a CR, but did not have a complete bone marrow assessment, were considered to have a PR.

The results of the study demonstrated a higher ORR and a longer PFS for Treanda (ORR - 68%) compared to chlorambucil (ORR - 33%); p <0.0001. The median PFS was 21 months in the Treanda treatment group, compared to 9 months in the chlorambucil treatment group; hazard ratio 0.26. The total number of deaths reported during the study was 19% of patients in the Treanda-treatment group and 26% of patients in the chlorambucil-treatment group. The hazard ratio is 1.38 (95% CI: 0.78, 2.46; p = 0.18) indicating no appreciable difference in survival between the two treatment arms. There were no significant differences in the overall QoL between the Treanda and chlorambucil treatment groups as measured by global health status.

Overall, Treanda is efficacious in the treatment of patients with symptomatic CLL and has a manageable safety profile when used as a first-line therapy. There was a significant improvement in ORR and PFS compared to chlorambucil, an approved agent for treatment of patients with CLL in Canada. A statement has been added to the Product Monograph indicating that efficacy relative to first-line therapies other than chlorambucil has not been established. This is important because fludarabine regimens are now used in the clinical setting as the preferred first-line treatment for many patients who are able to tolerate this treatment which would have included a significant portion of the patients enrolled into both arms of this clinical study.

3.3.4 Clinical Safety

The clinical safety of Treanda was evaluated in the clinical studies described in section 3.3.3 Clinical Efficacy.

Non-Hodgkin's Lymphoma (Indolent Disease)

Patients with B-cell indolent NHL received a higher and more frequent dose of Treanda monotherapy compared to CLL patients in the pivotal clinical studies. The adverse event (AE) profile for indolent NHL patients follows administration of a 120 mg/m² dose of Treanda on Days 1 and 2 of a 21-day cycle for a maximum of 8 cycles. The median total dose was 1,410 mg/m² with a median duration of treatment of 107 days (range 2 to 233 days). Haematologic laboratory abnormalities were commonly identified as AEs following administration of Treanda. The most common haematological AEs were neutropaenia (45%), anaemia (37%), thrombocytopaenia (36%), and leukopaenia (16%).

The most common non-haematologic AEs (≥30%) were nausea (77%), fatigue (64%), diarrhoea (42%), vomiting (40%), pyrexia (36%) and constipation (31%). The most common non-haematologic Grade 3 or 4 AEs (≥5%) were fatigue (14%), febrile neutropaenia (6%), and pneumonia, hypokalaemia, diarrhoea, and dehydration, each reported in 5% of patients. Antiemetics were concomitantly administered to 96% of patients.

Serious AEs (SAEs), regardless of causality, were reported in 39% of NHL patients receiving Treanda. The most common SAEs occurring in ≥5% of patients were febrile neutropaenia and pneumonia. Other important SAEs reported were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. The most common reason for dose delay was neutropaenia. Thirty-one (31) patients had AEs with reported outcomes of discontinuation of study drug treatment. The most common events with this outcome were thrombocytopaenia (9%), fatigue (6%), and neutropaenia (4%).

A Serious Warnings and Precautions box was included in the Product Monograph describing the following clinically significant SAEs associated with the use of Treanda: myelosuppression; infections, including fatalities; and second malignancies. Treanda should not be used in patients with serious infections. Treanda should be administered under the supervision of a qualified health professional who is experienced in oncology.

The recommended dose is close to the maximum tolerated dose (MTD) for this schedule (Days 1 and 2 every 21 days) as established in Phase I clinical studies. Dose delays, reduction and discontinuation plans have been implemented for this dosing regimen to help ensure the safety of the indolent NHL population receiving this therapy while trying to maintain a dose that can achieve an active tumour response. In total, sixty-eight (68%) patients had AEs causing dose reduction, interruption or discontinuation. The most common reason for dose delay was neutropaenia. Thirty-one patients had AEs with reported outcomes of discontinuation of study-drug treatment. The most common events with this outcome were thrombocytopaenia (9%), fatigue (6%), and neutropaenia (4%).

At least one pneumonia related death was due to cytomegalovirus (CMV) infection. Wording has been added to the Product Monograph indicating that patients and physicians should closely monitor for signs of infection and in the case of fever of unknown origin, CMV testing should be performed. Although CMV testing is not recommended at baseline, there is the possibility that CMV-related pneumonia may occur as a result of reactivation since 12% of patients in this study had documented cases of herpes zoster (shingles) infection due to reactivation of the latent varicella-zoster virus.

Cardiac-related AEs, irrespective of any association with Treanda, were reported in 16 (16%) patients. Grade 1 or 2 tachycardia was the most common event (5%) and Grade 1 palpitations occurred in 3% of patients. More serious events included myocardial infections (3%), cardiorespiratory arrest (2%), and sinus tachycardia (2%). At least one case of sinus tachycardia was considered possibly related to Treanda. Importantly, both hyper and hypokalaemia were reported in the clinical studies. Electrolyte imbalances can impact on cardiac function, particularly in patients with underlying disease. Eleven percent (11%) of patients in the NHL study had hypokalaemia and of these, 6% were Grade 3. Wording has been added to the Product Monograph indicating that electrolytes should be monitored regularly (along with complete blood counts), as well as recommending that patients with pre-existing cardiac disease and low serum potassium have periodic ECG monitoring.

Tumour lysis syndrome is a potentially serious condition that has occurred with Treanda and is captured in the Product Monograph. These events occurred more commonly in CLL patients but one Grade 3 event occurred in an NHL patient in the pivotal study. Tumour lysis is considered treatment related and should be monitored during the first few cycles by measuring serum chemistries (uric acid, potassium, LDH, etc.). Tumour lysis releases potassium from internal stores and can result in hyperkalaemia which was also reported in the study (2%).

Treanda is not recommended for patients with moderate to severe renal or hepatic impairment. Studies have not been performed to evaluate the pharmacokinetics of Treanda in these patients. Five percent (5%) of patients had elevated blood creatinine levels; one (1%) was Grade 3. Acute renal failure was reported in 2 patients in the pivotal study; one case was not considered treatment related. The Product Monograph has been updated to reflect this information.

Overall, Treanda at the chosen dose and schedule showed variable tolerability among the patients enrolled in this study. Some patients required significant dose delays and reductions due to haematological toxicities. In fact, the majority (68%) of patients required either dose delays, reductions and in some cases discontinuations due to AEs. Treanda significantly impacted the gastrointestinal and blood/lymphatic systems. Nausea and vomiting occurred frequently despite prophylactic use of antiemetics. In addition, fatigue was experienced by the majority of NHL patients treated with Treanda, including 14% with Grade 3 or 4 AEs. Thrombocytopaenia (9%) was the most common reason for discontinuation, followed by fatigue (6%), and neutropaenia (4%). Treatment-related fatalities, primarily due to infections, were a significant concern in the pivotal study.

Some NHL patients may not tolerate Treanda at the 21-day regimen. A statement has been added to the Product Monograph stating that Treanda is not recommended for a subset of relapsed indolent NHL patients with poor tolerance to prior therapies (including other alkylating agents) as they would not be expected to tolerate the 120 mg/m² dose administered on Days 1 and 2 of a 21-day cycle. The efficacy and safety of other dosing regimens for these patients has not been established.

Chronic Lymphocytic Leukaemia

Patients with CLL were administered a 100 mg/m² dose of bendamustine HCl on Days 1 and 2 of a 28-day cycle for a maximum of 6 cycles. The median total dose was 1,010 mg/m² with a median duration of treatment of 142 days (range 2 to 211 days). Haematologic AEs were significant and reported in greater numbers for Treanda compared to chlorambucil: neutropaenia (27% vs. 14%); thrombocytopaenia (23% vs. 21%); anaemia (19% vs. 13%); and leukopaenia (17% vs. 3%).

Red blood cell transfusions were administered to 20% of patients receiving Treanda compared with only 6% of patients receiving chlorambucil. Non-haematologic AEs in the CLL study that occurred with a frequency >15% in the Treanda group were pyrexia (25%), nausea (19%), and vomiting (16%). Antiemetics were taken concomitantly by 37% of patients in the Treanda-treatment group compared to only 4% in the chlorambucil control group.

The most common Grade 3 or 4 non-haematological AEs reported for the Treanda-treatment group in CLL were pyrexia, pneumonia, infection, hyperuricaemia, rash, and hypertensive crisis (each 2%) and hypertension (3%). Worsening hypertension was reported in 4 patients treated with Treanda in the randomized CLL clinical study as compared to none in the chlorambucil-treatment group. Three of these four AEs were described as a hypertensive crisis and were managed with oral medications and resolved.

Hypertension should be well-controlled prior to administration of Treanda.

The most frequent AEs leading to study withdrawal for patients receiving Treanda were hypersensitivity (2%), pyrexia (1%) and rash (1%). As discussed above for NHL, tumour lysis syndrome has been reported following treatment with Treanda and occurred with a greater frequency in the CLL study. Appropriate labelling to describe this risk has been added to the Product Monograph.

Potential Treanda-related effects on hepatic function were observed more frequently with CLL patients compared to indolent NHL patients. Thirty-four percent (34%) of Treanda-treated patients had bilirubin elevations, some without associated significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with Treanda may also have changes in their creatinine levels. Appropriate labelling has been included in the Product Monograph to restrict the use of Treanda in patients with moderate or severe hepatic impairment.

There were three SAEs of drug hypersensitivity reported for Treanda; two of the three cases resulted in discontinuation. Treanda is contraindicated in patients who are hypersensitive to bendamustine HCl or any ingredient in the formulation, including mannitol, or component of the container.

Overall, there were safety concerns with the recommended dose for the CLL patient population. All important safety risks reported in studies with Treanda are managed through strict labelling.

Other Safety Concerns

In the NHL and CLL populations, there were no clinically significant differences in efficacy and in the adverse reaction profile between geriatric (≥65 years of age) and younger patients. The safety and effectiveness of Treanda in paediatric patients have not been established.

Extravasation

There are post-marketing reports of bendamustine HCl extravasations resulting in hospitalizations from erythaema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of Treanda.

Carcinogenesis and Mutagenesis

Pre-malignant and malignant diseases have developed in patients treated with Treanda including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia, and bronchial carcinoma. Bendamustine HCl is mutagenic, genotoxic and carcinogenic with cancers reported following subcutaneous and oral delivery of the drug to mice.

Electrocardiogram Changes, including QTc prolongation

The potential for Treanda to cause QTc prolongation has not been studied. Isolated cases of ECG changes have been observed in patients administered Treanda at a dose higher than recommended for NHL and CLL patients. In non-clinical in vitro cardiac safety studies, Treanda inhibited hERG-1 tail current amplitude but had no effect on the cardiac action potential in isolated canine Purkinje fibres.

Infusion Reactions and Anaphylaxis

Infusion reactions to Treanda have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy

Skin

A number of skin reactions have been reported in clinical studies and post-marketing safety reports. These events have included rash, toxic skin reactions, and bullous exanthema. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some fatal, have been reported when Treanda was administered with allopurinol and there may be an increased risk of severe skin toxicity when the two agents are administered concomitantly.

3.3.5 Additional Issues

Monitoring and Laboratory Tests

Prior to initiating treatment with Treanda, complete blood counts (CBC), renal (creatinine) and liver [AST, ALT, bilirubin and alkaline phosphatase (ALP)] function tests, electrolytes, blood pressure and hepatitis B testing should be performed and/or measured.

During treatment with Treanda, CBC and electrolytes should be measured at regular intervals and CBC more frequently in patients who develop cytopaenias. Patients and physicians should closely monitor for signs of infection and in the case of fever of unknown origin CMV testing should be performed. Signs of tumour lysis syndrome should be monitored where warranted. Periodic ECG monitoring should be performed in patients with cardiac disorders, particularly in the event of electrolyte imbalances. Monitoring of liver and renal functions, blood pressure and blood sugar should also be performed periodically.