1
`
`Product Monograph
`
`updated 01/2002
`
`bendamustine
`
`AGILA ET AL - EXHIBIT 1014
`
`

`
`C
`
`Table of contents
`
`1.
`
`Historical review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
`
`2.
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`2.7
`
`Product description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`Description of the finished medicinal product . . . . . . . . . . . . . . . . . . . . . . . . 8
`Chemical name and structural formula of the active ingredient . . . . . . . . . . 8
`Presentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
`Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`Type of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
`Dosage by individual and daily doses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
`
`Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`3.
`Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`3.1
`Subchronic toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
`3.2
`3.3 Mutagenic and carcinogenic effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
`3.4
`Reproductive toxicity and teratogenic activity . . . . . . . . . . . . . . . . . . . . . . . 12
`
`Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
`4
`Efficacy in animal models and cell culture . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
`4.1
`4.2 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
`
`5.
`5.1
`5.2
`5.3
`5.4
`5.5
`5.6
`5.7
`5.8
`
`Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Site of absorption and absorption kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Protein binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Concentration in tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`CSF penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Placental transfer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Excretion in breast milk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
`Biological half-life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`
`3
`
`

`
`4
`
`

`
`Elimination in impaired renal function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`5.9
`5.10 Elimination in impaired hepatic function . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`5.11 Dialysability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
`5.12 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
`
`6.
`6.1
`6.2
`6.3
`6.4
`6.5
`6.6
`6.7
`6.8
`6.9
`
`Clinical efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
`Hodgkin’s disease (stage II-IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
`Non-Hodgkin lymphoma (NHL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
`Chronic lymphocytic leukemia (CLL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
`Plasmocytoma (multiple myeloma / MM) . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
`Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
`In clinical evaluation – lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
`In clinical evaluation – gastrointestinal tumours. . . . . . . . . . . . . . . . . . . . . . 39
`In clinical evaluation – head and neck cancer . . . . . . . . . . . . . . . . . . . . . . . . 40
`Effects on lymphocyte subsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
`
`Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
`7.
`General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
`7.1
`Hematopoietic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
`7.2
`Gastrointestinal tract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`7.3
`Nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`7.4
`Allergic reactions / hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`7.5
`Cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`7.6
`Skin, mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
`7.7
`Local irritations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
`7.8
`7.9 Other side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
`7.10 Note for drivers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
`
`Overdosage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
`8.
`8.1 Main symptoms and general signs of overdosage . . . . . . . . . . . . . . . . . . . . 46
`8.2
`Treatment of overdosage and intoxication . . . . . . . . . . . . . . . . . . . . . . . . . . 47
`
`9.
`
`Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
`
`10.
`
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
`
`11.
`
`Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
`
`Directions for Use for Physicians. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
`
`5
`
`

`
`6
`
`6
`
`

`
`1
`
`Historical review
`
`Bendamustine (IMET 3393) was developed in the early 1960s by
`Ozegowski and co-workers (44) at the Institute of Microbiological
`and Experimental Therapy in Jena (Germany).The aim of the synthesis
`was to combine a purine and amino acid antagonist with an alkylating
`nitrogen mustard group (bifunctional alkylating agent).A major
`advantage of the newly developed compound compared to chlorambu-
`cil, for example, was its water solubility (45).Anger et al. (2) published
`initial results of the successful clinical use of bendamustine in plasmo-
`cytoma patients. Bendamustine was marketed from 1971 to 1992
`under the trade name Cytostasan® by the Jenapharm company. Since
`1993 the cytostatic is being marketed by ribosepharm GmbH under
`the name Ribomustin®.
`
`7
`
`

`
`2
`
`Product description
`
`2.1 Description of the finished medicinal product
`Ribomustin®
`Active ingredient: bendamustinehydrochloride
`
`2.2 Chemical name and structural formula of
`the active ingredient
`(5-[bis(2-chloroethyl)-amino]-1-methyl-2-benzimidazole) butyric acid hydro-
`chloride (Figure 1).
`
`Structural formula
`
`Cl-CH2-CH2
`
`Cl-CH2-CH2
`
`N
`
`N
`
`N
`
`(CH2)3-COOH•HCl
`
`CH3
`Figure 1: Structural formula of bendamustinehydrochloride
`
`Empirical formula
`C16H18Cl2N3O2•HCl
`
`Molecular weight
`394.7 (calculated with reference to the anhydrous substance)
`
`2.3 Presentation
`One vial with pierceable stopper with 55 mg of the dried substance contains
`25 mg of bendamustinehydrochloride.
`
`One vial with pierceable stopper with 220 mg of the dried substance contains
`100 mg of bendamustinehydrochloride.
`
`8
`
`8
`
`

`
`2.4 Indications
`Ribomustin® is indicated as single-agent therapy or in combination with other
`antineoplastic drugs for the treatment of the following malignancies:
`
`• Hodgkin’s disease (stages II-IV)
`• non-Hodgkin’s lymphoma
`• plasmocytoma
`• chronic lymphocytic leukemia
`• breast cancer.
`
`2.5 Contraindications
`Ribomustin® should not be used in the following cases:
`
`• known hypersensitivity to bendamustine and/or mannitol
`• pregnancy, presumed pregnancy and during breast feeding
`• impairment of renal function (glomerular filtration rate < 30 ml/minute)
`• severe liver parenchymal damage
`• jaundice
`• existing severe bone marrow depression and severe blood count abnormalities
`• major surgery less than 30 days before starting therapy
`• infections, especially associated with leukopenia (risk of generalization of infection).
`
`2.6 Type of use
`Ribomustin® is administered as a short intravenous infusion over 30 to 60 minutes
`after reconstitution in accordance with the instructions.
`
`The ready-to-use solution is prepared as follows:
`
`Dissolve the contents of one Ribomustin® vial with pierceable stopper containing
`25 mg bendamustine in 10 ml by shaking.
`Dissolve the contents of one Ribomustin® vial with pierceable stopper containing
`100 mg bendamustine in 40 ml by shaking.
`
`As soon as a clear solution is obtained (this usually takes 5 to 10 minutes), dilute the total
`dose of Ribomustin® immediately with 0.9 % NaCl solution to produce a final volume of
`about 500 ml.
`
`9
`
`

`
`2.7 Dosage by individual and daily doses
`Bendamustine is administered as monotherapy or in combination with other chemothera-
`peutic agents in a variety of dosages and regimens.There is no “standard dosage” and no
`“standard regimen”. Some widely used dosages and regimens which have been evaluated
`in clinical studies are given below. For further dosages and regimens please refer to the
`medical literature; information is also available on request.
`Treatment should be terminated if the leukocyte and/or platelet count has decreased to
`levels ≤ 3,000/µl and ≤ 75,000/µl respectively.
`Ribomustin® treatment can be continued after the leukocyte count has increased to ≥
`4,000/µl and the platelet count to ≥ 100,000/µl.
`The portion of free bendamustine hydrochloride may be increased by up to 30% if the level
`of albumin in plasma is very low (≤ 30 g/l).A dose reduction may therefore be considered
`in such cases. Examples of different dosages and regimens (depending on the indication):
`
`Hodgkin’s disease (stages II –IV)
`“DBVBe regimen”:
`daunorubicin
`25 mg/m2
`bleomycin
`10 mg/m2
`vincristine
`1.4 mg/m2
`Ribomustin®
`50 mg/m2
`
`Non-Hodgkin’s lymphoma
`“BOP regimen”:
`Ribomustin®
`vincristine
`prednisone
`
`60 mg/m2
`2 mg/m2
`100 mg/m2
`
`on days 1+15
`on days 1+15
`on days 1+15
`on days 1– 5
`
`on days 1– 5
`on day 1
`on days 1– 5
`
`repetition of the cycle after 4 weeks.
`
`repetition of the cycle after 3 weeks.
`
`Plasmocytoma
`“BP regimen”:
`Ribomustin®
`prednisone
`
`120–150 mg/m2 on days 1+2
`60 mg/m2
`on days 1– 4
`
`repetition of the cycle after 4 weeks.
`
`Chronic lymphocytic leukemia
`Ribomustin®
`80–100 mg/m2
`
`on days 1+2
`
`repetition of the cycle after 4 weeks.
`
`Breast cancer
`“BMF regimen”:
`120 mg/m2
`Ribomustin®
`40 mg/m2
`methotrexate
`600 mg/m2
`5-fluorouacil
`“Second line therapy”:
`Ribomustin®
`100–150 mg/m2 on days 1+2
`
`on days 1+8
`on days 1+8
`on days 1+8
`
`repetition of the cycle after 4 weeks.
`
`repetition of the cycle after 4 weeks.
`
`Note:
`No dose recommendations can currently be given for children, since there is no experience
`with this age group.
`
`10
`
`10
`
`

`
`3
`
`Toxicology
`
`3.1 Acute toxicity
`The LD50 in mice after intravenous and intraperitoneal administration is
`80 mg/kg body weight.The LD50 in rats after intravenous administration
`is 40 mg/kg body weight (62).
`
`3.2 Subchronic toxicity
`Bendamustine hydrochloride was administered orally to rats in dosages of 10,
`20, 40, 80 and 160 mg/kg daily over a period of 28 days.The substance was
`not lethal up to a dose of 40 mg/kg. Hematologic and non-hematologic side
`effects were slight to moderate and reversible after treatment termination.The
`LD50 was reached at dosages of ≥ 80 mg/kg daily.
`In dosages of 80 and 160 mg/kg bendamustine induced bone marrow aplasia,
`atrophy of lymphatic tissue and histopathologic abnormalities of the kidneys
`and intestine.There was no evidence of damage to other organs (33).
`
`Subchronic toxicity studies in dogs were performed with a 30-minute daily
`intravenous infusion administered in three 4-day cycles. Each of the cycles was
`followed by a 31-day recovery phase.The following side effects were observed
`at doses of 6.6 mg/kg/day: vomiting, salivation, weight loss and loss of appe-
`tite. During the recovery phase evacuation of liquid stool and behavioural
`changes were observed. Gross examination revealed mucosal hyperemia and
`intestinal hemorrhagic zones in these animals. Microscopic analysis also revea-
`led pronounced changes to lymphatic tissue as an indicator of immuno-
`suppression, and changes to kidneys, testes and prostate. Doses of 3.3 and
`1.65 mg/kg/day, however, were tolerated with only minor toxicity (slightly
`reduced food consumption, slight weight loss, dose-dependent leukocyte
`suppression) (11).
`
`11
`
`

`
`3.3 Mutagenic and carcinogenic effects
`Bendamustine induces chromosome aberrations and exhibits mutagenic activity in cell
`culture and animal models (22; 54; 55).
`
`Lung tumours and mammary carcinomas were detected in mice after administration of
`bendamustine (15).
`
`3.4 Reproductive toxicity and teratogenic activity
`Bendamustine was embryotoxic and teratogenic in pregnant mice (24).
`
`12
`
`12
`
`

`
`4
`
`Pharmacology
`
`4.1 Efficacy in animal models and cell culture
`Schnabel et al. (62) demonstrated with three experimental murine tumours
`(leukemia LAJ1, sarcoma 180, Ehrlich ascites carcinoma) that bendamustine is
`comparable to cyclophosphamide in its suppressive effect on tumour growth.
`
`Further studies (14) have evaluated the antineoplastic activity of bendamustine
`in 8 experimental murine tumour models using different transplantation tech-
`niques and forms of administration. Bendamustine exhibited a suppressive
`effect on tumour growth for 6 tumours (Ehrlich ascites carcinoma, leukemia
`L1210, leukemia P388, melanoma B16, Lewis lung carcinoma and lymphoma
`ABDt6) (4).
`
`Strumberg et al. (66) studied the cytotoxic effect of bendamustine on human
`ovarian and mammary carcinoma cell lines (including cisplatin and doxorubi-
`cin resistant cell lines). Besides the cytotoxic activity the investigators also
`demonstrated incomplete cross-resistance with other alkylating agents (cyclo-
`phosphamide, melphalan and carmustine).
`
`Schwaenen et al. (65) studied the in vitro induction of apoptosis in B-CLL
`cell lines by bendamustine and fludarabine alone and in combination. Benda-
`mustine showed dose-related apoptosis induction of 8% to 94% after 48 hours.
`
`13
`
`

`
`In 10 of 12 B-CLL cell lines the combination of bendamustine and fludarabine resulted
`in a synergistic effect after 48 hours, i.e. a 1.4-fold higher apoptosis rate than expected
`(see Figure 2).
`
`I fludarabine 0.7 (cid:181)g/ml
`I bendamustine 2 (cid:181)g/ml
`I expected
`I combination
`
`95,99
`
`88,42
`
`52,82
`
`41,87
`
`62,24
`
`33,75
`
`24,66
`
`17,21
`
`13,34
`
`1,07 3,39 4,46
`
`24 h
`
`48 h
`time
`
`72 h
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`apoptosis rate (%)
`
`Figure 2: Enhanced apoptosis of B-CLL lymphocytes on incubation with bendamustine / fludarabine (accor-
`ding to Schwaenen et al.)
`
`Chow et al. (12) studied the in vitro induction of apoptosis and inhibition of proliferation of
`neoplastic cells in low-grade NHL using combinations of established cytotoxic drugs with
`bendamustine.The combination of bendamustine with cladribine resulted in additive or
`even synergistic effects on apoptosis and inhibition of cell proliferation on all tested cell
`populations (DOHH-2;WSU-NHL; ex vivo cells of patients with CLL, leukemic low-
`grade B-NHL,T-NHL). In contrast, the combination of bendamustine with either doxoru-
`bicin or mitoxantrone showed antagonistic effects both on apoptosis and inhibition of cell
`proliferation (Figure 3).
`
`Combination index of tested drug combinations
`
`CI
`
`7.5
`
`5.0
`
`2.5
`
`0.0
`
`Antagonism
`CI>1
`
`Synergism
`CI<1
`
`14
`
`14
`
`A
`
`P
`
`A
`
`P
`
`A
`
`P
`
`B+D
`
`B+M
`
`B+C
`
`Figure 3: Combination index (CI) for apoptosis (A) and inhibition of proliferation (P).
`Drug combinations:
`B+ D: bendamustine + doxorubicin,
`B+ M: bendamustine + mitoxantrone,
`B+ C: bendamustine + cladribine
`
`

`
`Bendamustine induced apoptosis was p53 independent, thus the apoptosis cascade seems
`not to be influenced by bendamustine.Therefore, the expression patterns of the drug com-
`binations containing bendamustine depended on the expression caused by the combination
`partner (doxorubicin, mitoxantrone or cladribine).
`
`This cell model demonstrated that bendamustine has a different mechanism of interaction
`than that of purine analogs and a different manner of induction of apoptosis than alcylating
`agents.
`
`These results suggest that schedules using combinations of bendamustine and anthracy-
`clines should not be recommended for the treatment of low-grade NHL, whereas benda-
`mustine combined with cladribine could be considered for the development of future
`treatment strategies.
`
`Schleucher et al. (61) studied the interaction of bendamustine with vinorelbine, 5-FU and
`paclitaxel in cytotoxicity assays. In addition, he studied whether the efficiency is influenced
`by the sequence of the drugs.
`Bendamustine showed significant cytotoxicity in human tumour cell lines, even in those
`with MDR-1 activity.The sequence of bendamustine and 5-FU showed additive to syner-
`gistic interactions. Bendamustine and vinorelbine showed a sequence dependent synergism
`in 2 different cell lines.The cytotoxic activity of paclitaxel may be increased in combinati-
`on with bendamustine.
`
`MDA-MB231
`
`MCF-7
`
`Interactions of the cytotoxic agents bendamustine, 5-FU, paclitaxel, and vinorelbine
`on breast cancer cell lines MCF-7 (wild type) and MDA-MB231ª
`synergistic
`MCF-7
`bendamustine before 5-FU
`additive
`5-FU before bendamustine
`synergistic
`bendamustine before 5-FU
`antagonistic
`5-FU before bendamustine
`synergistic
`bendamustine before paclitaxel
`antagonistic
`paclitaxel before bendamustine
`antagonistic
`bendamustine before paclitaxel
`synergistic
`paclitaxel before bendamustine
`synergistic
`bendamustine before vinorelbine
`synergistic
`vinorelbine before bendamustine
`synergistic
`bendamustine before vinorelbine
`synergistic
`vinorelbine before bendamustine
`ª incubations with bendamustine, paclitaxel, and vinorelbine for 2 h, with 5-FU for 24 h
`
`MB231
`
`MCF-7
`
`MDA-MB231
`
`15
`
`

`
`4.2 Mechanism of action
`Bendamustine is a bifunctional alkylating agent with antineoplastic and cytocidal properties
`(Figure 4).
`
`benzimidazole ring:
`purine analogue
`
`C
`
`C
`
`C
`
`C
`
`C O
`O
`
`N N
`
`C C
`
`C
`C
`
`C
`
`C
`
`C N
`
`C C
`
`C
`
`C
`
`C
`
`C
`
`N-mustard-group:
`alkylating agent
`(reduced toxicity due
`to electron affinity)
`
`alkanecarboxylic acid:
`provides water-solubility
`
`Figure 4: Chemical-functional structure of bendamustine
`
`The efficacy is attributable mainly to crosslinking of the DNA single and double strands by
`alkylation.This produces a disturbance of the matrix function of DNA and DNA synthesis.
`There is also crosslinking between DNA and proteins and between proteins themselves.
`It is not yet known whether the benzimidazole ring possesses additional antimetabolite pro-
`perties (18; 30; 66; 68).
`
`16
`
`

`
`5
`
`Pharmacokinetics
`
`5.1 Site of absorption and absorption kinetics
`Not applicable since intravenous administration.
`
`5.2 Protein binding
`The substance is bound to plasma proteins (preferentially albumin) to the
`extent of 95% (16; 41; 42).The protein binding behaviour of bendamustine
`has been shown to be unaffected by low plasma albumin levels, age over
`70 years and advanced tumour stages (15).
`
`5.3 Concentration in tissue
`No cumulation is to be expected (42; 47).
`
`5.4 CSF penetration
`No information is available regarding CSF penetration.
`
`5.5 Placental transfer
`No information is available regarding placental transfer.
`
`5.6 Excretion in breast milk
`No information is available regarding excretion in breast milk.
`
`17
`
`

`
`5.7 Biological half-life
`Following i. v. bolus injection of bendamustine in the usual therapeutic dosages, the plasma
`level in man follows a biphasic exponential pattern.The elimination half-life t1/2α is bet-
`ween 6 and 10 minutes, and the terminal elimination half-life t1/2ß between 28 and 36
`minutes.After i. v. administration in several studies the central volume of distribution was
`between 8.6 and 11.2 l. Under steady state conditions the volume of distribution was
`15.8 – 20.5 l (41; 42).
`
`5.8 Elimination
`Elimination is rapid, biphasic and predominantly renal. Mean total clearance was calculated
`as 528.9 – 826.2 ml/minute.The following fractions, referred to the total amount of admi-
`nistered parent compound, were detected in urine: bendamustine 45.3%, hydroxy-benda-
`mustine 23.8%, an unidentified polar metabolite 13.4%, ß-hydroxy-bendamustine 8%, an
`unidentified apolar metabolite 5.1% and N-demethyl-bendamustine 1.5%. Mainly polar
`metabolites are eliminated by the biliary route (41; 42).
`
`5.9 Elimination in impaired renal function
`Bendamustine is predominantly eliminated by the renal route.The drug should
`not be given to patients with impaired renal function (glomerular filtration rate
`< 30 ml/minute).
`
`5.10 Elimination in impaired hepatic function
`Bendamustine is metabolized in the liver and eliminated to a small extent (mainly polar
`metabolites) via the biliary system.The drug should not be given to patients with severe
`hepatic parenchymal damage and jaundice.
`
`5.11 Dialysability
`It is not yet known whether bendamustine or its metabolites are dialyzable.
`
`18
`
`18
`
`

`
`19
`
`5.12 Metabolism
`Bendamustine is metabolized mainly in the liver.The main biotransformation product is a
`cytotoxic hydroxy derivative (ß-hydroxybendamustine), which is formed by hydroxylation
`of the butanoic acid side chain.This substance shows elimination kinetics similar to those
`of the parent compound (t1/2 about 19 minutes). In the dose range 0.5–5.0 mg/kg, clearan-
`ce and the AUC (ß-OH-bendamustine)/AUC (bendamustine) ratio are non-dose depen-
`dent. Further identified metabolites are monohydroxybendamustine, dihydroxybendamusti-
`ne, hydroxy-ß-hydroxybendamustine and N-demethylbendamustine (41; 42; 48) (Figure 5).
`
`ClCH2CH2
`
`ClCH2CH2
`
`N
`
`N
`
`N
`
`CH2CHOHCH2COOH
`
`CH3
`β-OH-bendamustine
`
`HOCH2CH2
`
`ClCH2CH2
`
`N
`
`N
`
`N
`
`CH2CHOHCH2COOH
`
`ClCH2CH2
`
`ClCH2CH2
`
`N
`
`CH2CH2CH2COOH
`
`N
`
`N
`
`CH3
`bendamustine
`
`ClCH2CH2
`
`ClCH2CH2
`
`N
`
`N
`
`CH2CH2CH2COOH
`
`HN
`
`N-demethylbendamustine
`
`HOCH2CH2
`
`ClCH2CH2
`
`N
`
`N
`
`N
`
`CH2CH2CH2COOH
`
`CH3
`OH-bendamustine
`
`OHCH2CH2
`
`OHCH2CH2
`
`N
`
`N
`
`N
`
`CH2CH2CH2COOH
`
`CH3
`di-OH-bendamustine
`
`polar metabolite (I)
`polar metabolite (II)
`apolar metabolite (III)
`
`CH3
`OH-β-OH-bendamustine
`
`Figure 5: Metabolism of bendamustine (acc. to Preiss et al.)
`
`

`
`6
`
`Clinical efficacy
`
`6.1 Hodgkin’s disease (stage II-IV)
`Initial research findings have shown that bendamustine is at least as effective as cyclo-
`phosphamide (3).
`
`In a further prospective randomized study, Höche et co-workers (31) compared various
`chemotherapy protocols in 73 evaluable patients with Hodgkin’s disease stage IIIB or
`IV (Ann Arbor classification). Only patients with primary or secondary resistance to the
`CVPP regimen (cyclophosphamide / vinblastine / procarbazine / prednisone) were
`enrolled in the study. One treatment cycle lasted 28 days, and day 16 to day 28 were
`treatment-free.
`
`Treatment regimens
`DBVB (n = 38)
`Daunorubicin
`Bleomycin
`Vincristine
`Bendamustine
`
`25 mg/m2 i.v. on days 1 + 15
`10 mg/m2 i.v. on days 1 + 15
`1.4 mg/m2 i.v. on days 1 + 15
`50 mg i.v. on days 1 – 5
`
`ABVD (n = 35)
`Doxorubicin
`Bleomycin
`Vincristine
`Dacarbazine
`
`25 mg/m2 i.v. on days 1 + 15
`10 mg/m2 i.v. on days 1 + 15
`1.4 mg/m2 i.v. on days 1 + 15
`150 mg/m2 i.v. on days 1 – 5
`
`Study results
`
`Number of
`patients
`
`CR
`n (%)
`
`CR + PR
`n (%)
`
`DBVB
`ABVD
`
`38
`35
`
`9 (24)
`4 (11)
`
`26 (69)
`29 (83)
`
`Median
`remission
`duration
`(months)
`4.5
`3.4
`
`Median
`survival
`
`(months)
`19.5
`11.3
`
`20
`
`20
`
`

`
`Conclusions:The combination therapy containing bendamustine is equivalent in effective-
`ness to the reference therapy but is better tolerated.
`
`Herold et al. (25) evaluated the efficacy of cyclic alternating chemotherapy in the therapy
`of patients with non-pretreated advanced Hodgkin’s disease (stage IIIA, IIIB, IVA, IVB)
`in a multicentre randomized study.
`
`Treatment regimens
`CVPP (n = 40)*
`Cyclophosphamide
`Vinblastine
`Procarbazine
`Prednisolone
`
`600 mg/m2 i.v. on days 1 + 8
`6 mg/m2 i.v. on days 1 + 8
`100 mg oral on days 1 – 14
`40 mg/m2 oral on days 1 – 14
`
`DBVB – alternating with the above CVPP regimen (n = 40)**
`Daunorubicin
`25 mg/m2 i.v. on days 1 + 15
`Bleomycin
`10 mg/m2 i.m. on days 1 + 15
`Vincristine
`2 mg i.v. on days 1 + 15
`Bendamustine
`30 mg/m2 i.v. on days 1 - 5
`* treatment-free interval day 15 to day 28; prednisolone only in cycles 1 and 4
`** treatment-free interval day 16 to day 28
`
`The results of this treatment demonstrate that the two therapeutic regimens are equally
`effective. No statistically significant differences were detectable.
`
`Study results
`
`CVPP
`
`Number of
`patients
`40
`
`CR
`n (%)
`24 (60)
`
`PR
`n (%)
`6 (15)
`
`CR + PR
`n (%)
`30 (75)
`
`No
`remission
`10 (25)
`
`DBVB – alternating with the above CVPP regimen
`40
`23 (57.5)
`12 (30)
`
`35 (87.5)
`
`5 (12.5)
`
`With the aim of reducing the risk of late complications of combined radiochemotherapy
`in patients with non-pretreated Hodgkin’s disease and of minimizing risk factors, Herold
`et al. (26; 27) studied the efficacy of reduced radio- and chemotherapy as sandwich therapy.
`The following parameters were regarded as particular risks: large mediastinal tumour,
`B-symptoms, extensive abdominal involvement, extranodal involvement – especially of
`the lungs –, unfavourable histologic subtypes – especially lymphocyte-depleted histologic
`subtypes –, increase in sedimentation rate of more than 50 mm in the first hour.
`The therapeutic regimen developed in the pilot study is shown below.
`
`21
`
`

`
`Therapeutic regimen
`CVPP/ABVCy hybrid regimen
`Cyclophosphamide
`600 mg/m2 i.v. on day 1
`Vinblastine
`6 mg/m2 i.v. on day 1
`Procarbazine
`100 mg/m2 oral on days 1 – 7
`Prednisolone
`40 mg/m2 oral on days 1 – 14
`Doxorubicin
`25 mg/m2 i.v. on day 8
`Bleomycin
`15 mg/m2 i.m. on day 8
`Vincristine
`2 mg i.v. on day 8
`Bendamustine
`30 mg/m2 i.v. on days 8 – 12
`Treatment-free interval day 15 to day 28; repetition day 29
`
`Radiotherapy was administered with a reduced focal dose of 25 Gy as involved field
`irradiation, and chemotherapy comprised six cycles.
`
`In addition to the favourable results in terms of remission rate (81% patients with CR, 12%
`with PR and only 7% non-responders) the 9-year survival data of the pilot study are signi-
`ficant.
`
`After a median observation period of 108 months, 27 of 35 patients are in their first com-
`plete remission. Eight patients relapsed (after 14, 20, 30, 31, 36, 38, 48 and 77 months).
`Renewed complete remission could be achieved in 3 of these 8 patients by salvage therapy.
`The proportion of patients classifiable as responders (= rate of freedom from therapeutic
`failure) was 78% (after 5 years) and 70% (after 9 years).Total survival after 5 and 9 years was
`83% and 73% respectively.
`
`In a subsequent phase III study (28), 100 non-pretreated patients were treated with either
`cyclophosphamide or bendamustine, each combined with vinblastine, procarbazine, predni-
`solone, doxorubicin, vincristine and bleomycin and also received radiotherapy.The results
`of the above pilot study were confirmed. Comparable remission and survival rates were
`determined for both therapeutic regimens.The CR rate was 88% in the bendamustine
`group and 81% in the cyclophosphamide group.The 5-year total survival rate at interim
`analysis (68 months follow-up) was 83% and 80% respectively (bendamustine and cyclo-
`phosphamide group).
`
`6.2 Non-Hodgkin lymphoma (NHL)
`
`6.2.1Indolent lymphoma
`Ruffert et al. (56) studied the efficacy of bendamustine in combination with vincristine
`and prednisolone (BOP) in 31 patients with refractory, progressive, malignant NHL (see
`table).
`
`22
`
`22
`
`

`
`Patient characteristics
`Stages
`11
`III A / III B
`20
`IV A / IV B
`Histology according to Kiel classification
`Low grade
`10
`Intermediate grade
`12
`High grade
`9
`Previous treatment
`Knospe
`COP
`CHOP-Bleo
`Relapse rate
`1st relapse
`2nd relapse
`3rd relapse
`
`9
`23
`15
`
`14
`8
`9
`
`Treatment regimen
`Chemotherapy was given according to the following regimen (repetition day 22):
`
`Bendamustine
`
`Vincristine
`Prednisolone
`
`60 mg/m2 i.v. as a short infusion over 1 hour on days 1 – 5
`or 100 mg/m2 i.v. on days 1 – 3
`1.4 mg/m2 i.v. on day 1 (up to max. 2 mg)
`100 mg/m2 i.v. on days 1 – 5
`
`The study results conclusively show the effectiveness of the treatment regimen as a second-
`line or third-line therapy in patients with Knospe, COP and CHOP-Bleo refractory malig-
`nant NHL.
`
`Study results
`
`Number of
`patients
`31
`
`CR
`n (%)
`12 (38.7)
`
`PR
`n (%)
`16 (51.6)
`
`CR + PR
`n (%)
`28 (90.3)
`
`NC
`n (%)
`0 (0)
`
`PD
`n (%)
`3 (9.6)
`
`The patients with complete remission showed a remission duration of 5 to 24+ months
`(median 12.4 months) and patients with PR showed a remission duration of 1 to 19 months
`(median 9.8 months).The total survival rate was 68% for the observation period. Malignant
`NHL was only in 13% of the patients the cause of death.
`
`23
`
`

`
`Evaluation of the study results taking into account the malignancy-grade showed that
`although no complete remissions were achieved for low-grade NHL, all patients achieved
`partial remission.The remission duration was between 3 and 19 months.
`
`Six and five patients with intermediate or high-grade NHL, respectively, achieved complete
`remission, and 5 and 2 patients, respectively, achieved partial remission.The results obtained
`in these patient samples are particularly to be emphasized since these patients had previous-
`ly been given both the COP and the CHOP-Bleo regimen. It can therefore be assumed
`that no cross-resistance to cyclophosphamide, doxorubicin and chlorambucil was present
`(see also 59). Subjective tolerability was very good (see table below).
`
`Toxicities
`Organ (incidence)
`
`Hemoglobin (6.4%)
`Granulocytes (35.4%)
`Platelets (16.1%)
`Bleeding (0%)
`Liver enzymes (0%)
`Stomatitis (9.6%)
`Nausea/vomiting (19.3%)
`Diarrhea (16.1%)
`Alopecia (0%)
`Infections (16.1%)
`Fever (16.1%)
`Exanthem (12.9%)
`Hypotension (12.9%)
`Phlebitis (35.4%)
`* Pneumonia, herpes zoster, cystopyelitis
`** Thrombophlebitis after intravenous bolus injection
`
`0
`29
`20
`26
`31
`31
`28
`25
`26
`31
`26
`26
`27
`27
`20
`
`WHO grade
`2
`1
`2
`3
`0
`0
`2
`4
`2
`0
`3*
`4
`1
`2
`3**
`
`1
`1
`4
`2
`0
`0
`1
`2
`3
`0
`0
`0
`3
`2
`6
`
`3
`0
`4
`0
`0
`0
`0
`0
`0
`0
`2*
`1
`0
`0
`2**
`
`4
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`In an ongoing study (21; 9), 39 pretreated patients with relapsed and advanced low-grade
`NHL have so far been treated with 120 mg/m2 bendamustine given as a short infusion over
`1 hour on days 1 and 2. Previous treatment comprised cyclophosphamide, ifosfamide,
`anthracyclines, chlorambucil, etoposide and vinca alkaloids. Complete remission has been
`observed in 4 of 32 patients so far evaluable. 53% of the patients showed partial remission
`(17 patients) and 19% (6 patients) were found to have a stable NC status.The current
`median remission duration is 10+ months. Side effects have generally been mild and were
`limited to myelosuppression, gastrointestinal toxicity and allergic reactions (see following
`table).
`
`24
`
`24
`
`

`
`Side effects (Heider et al.)
`Toxicity
`
`Leukocytes
`Platelets
`Hemoglobin
`Nausea/vomiting
`Allergies
`Cardiotoxicity
`Neurotoxicity
`Alopecia
`
`0
`5
`25
`8
`20
`39
`43
`43
`43
`
`WHO grade
`2
`10
`3
`8
`5
`3
`0
`0
`0
`
`1
`25
`15
`27
`18
`1
`0
`0
`0
`
`3
`3
`0
`0
`0
`0
`0
`0
`0
`
`4
`0
`0
`0
`0
`0
`0
`0
`0
`
`In an open label single centre pilot study,Weide et al. (67) evaluated a new effective treat-
`ment for refractory or relapsed indolent lymphomas with the combination of bendamusti-
`ne/mitoxantrone/rituximab (BMR). 31 patients received the BMR-regimen.
`
`Patient characteristics
`The median age of the patients was 67 (range 32-82). Median number of previous treat-
`ment regimens was 2 (1-6). 4 patients were refractory to fludarabine treatment.
`
`Secondary high grade lymphoma
`Indolent lymphoma
`
`B-PLL
`B-CLL
`
`n=5
`n=17
`
`n=1
`n=8
`
`Stage II: n=1
`Stage III: n=2
`Stage IV: n=19
`Ra