Table of contents
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`1.
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`Historical review . .
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`2.
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`2.2
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`Product description .
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`Description of the finished medicinal product .
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`Chemical name and structural formula of the active ingredient .
`Presentation .
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`2.4
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`2.5
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`Indications .
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`Contraindications .
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`Type of use . .
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`2.6
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`2.7
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`Dosage by individual and daily doses .
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`3.
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`3.1
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`Toxicology .
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`Acute toxicity .
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`3.2
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`Subchronic toxicity .
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`3.3 Mutagenic and carcinogenic effects .
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`3.4
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`Reproductive toxicity and teratogenic activity .
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`4
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`4.1
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`Pharmacology .
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`Efficacy in animal models and cell culture .
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`r 4.2 Mechanism ofaction . .
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`Pharmacokinetics .
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`5.
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`5.1
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`Site of absorption and absorption kinetics . . .
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`Protein binding .
`5.2
`5.3 Concentration in tissue .
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`5.4
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`CSF penetration .
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`5.5
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`5.6
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`5.7
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`5.8
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`Placental transfer .
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`Biological ha|f~|ife .
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`3
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`FRESENIUS KABI 1005-0002
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`FRESENIUS KABI 1005-0003
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`5.9
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`Elimination in impaired renal function .
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`5.10 Elimination in impaired hepatic function .
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`5.11 Dialysability .
`5.12 Metabolism .
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`5.1
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`Clinical efficacy .
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`6.3
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`Non-Hodgkin lymphoma (NHL)
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`5.4
`5.5
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`Plasmocytoma (multiple myeloma I MM)
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`6.6
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`In clinical evaluation — lung cancer .
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`5.7
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`6.9
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`In clinical evaluation — gastrointestinal tumours .
`In clinical evaluation — head and neck cancer .
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`7.
`?.1
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`Tolerability .
`General .
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`?.2 Hematopoietic system .
`7.3 Gastrointestinal tract .
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`Nervous system .
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`. 44
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`. 44
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`7.5 Allergic reactions! hypersensitivity .
`
`?.5
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`Cardiovascular system .
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`. .45
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`7.?
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`Skin, mucosa .
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`. 45
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`7.8
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`Local irritations .
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`. 45
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`7.9 Other side effects .
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`"1210 Note for drivers .
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`. . .
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`. 46
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`3.
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`overdosage .
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`8.1 Main symptoms and general signs of overdosage .
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`. 45
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`. 4?
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`8.2
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`Treatment of overdosage and intoxication .
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`9.
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`Summary .
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`, 48
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`. 49
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`10.
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`References .
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`. 55
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`11. Abbreviations .
`
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`Directions for Use for Physicians .
`
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`. .. 55
`
`FRESENIUS KABI 1005-0004
`
`

`
`FRESENIUS KABI 1005-0005
`
`

`
`Historical review
`
`Bendantustine (LMET 3393) was developed in the early 1960s by
`
`Ozegowski and co—workers (44) at the Institute of Microbiological
`
`and Experimental Therapy in Jena (Get-n1any).Tl1e 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 ex3n1ple,was its water solubility (45).Ange1- et al- ('3) published
`
`initial results of the successful clinical use ofbendaimistine in plasma-
`
`cytotna patients. Bendamustine was marketed fi-om 1971 to 1992
`
`under the trade I'1‘3.IIIlf: Cytostaaaxfi’ by thejenapharrn tzompany. Since
`
`1993 the eytostatic is being marketed by ribosepharm GrnbH under
`the name Rjbomtlstin’.
`
`FRESENIUS KABI 1005-0006
`
`

`
`
`
` Product description
`
`2.1 Description of the finished medicinal product
`Ribomustinm
`
`Active ingredient:bendarnustinehyd.roci1.loride
`
`2.2 Chemical name and structural formula of
`
`the active ingredient
`(5—'[bis(2—chIoroethyl)—2m1ino]—1—mcthyl-L’—benzimjdazolc) butyric acid hydro-
`
`chloride (Figure: 1).
`
`Structural formula
`
`Cl-CH;-CH2-..\ N
`cI-cH.—cH,/
`
`N
`
`N
`
`>—(CHJ.-COOH-HCI
`
`Figure 1: Structural formula of bendarnustinahydrochlorida
`
`CH,
`
`Empirical formula
`
`C,.,H,,,Cl,N3O;-HC1
`
`Molecular weight
`
`394.7 {calculated with reference to the anhydrous substance)
`
`2.3 Presentation
`
`One vial with pierceable stopper with 5:": mg of the dried substance contains
`
`25 mg of be-tidamustiiiehydrochloride-
`
`One vial with pierceable stopper with 220 mg of the dried substance contains
`
`100 mg ofbendamustinchydrochlot-idc.
`
`FRESENIUS KABI 1005-0007
`
`

`
`2.4
`
`Indications
`
`Ribomustin“ is indicated as single—agent therapy or in combination with other
`
`antineoplastie drugs For the treatment oiithe following malignancies:
`
`- Hodgkin's disease (stages II—lV)
`
`' non-I iodgkiifs lvlnphoma
`
`- plas11'1oeytom-.1
`
`' elironie lymphoeytie leukemia
`- breast cancer.
`
`2.5
`
`Contraindications
`
`Rihomustirr” should not be used in the following cases:
`
`° known hypersensitivity to bendalnustine :1nd/ or m'.mnitol
`
`0 pt-eg'naneyi presumed pregnancy and during breast Feeding
`
`0 ilitpairment often-.11 function (glomertilar filtration rate < 30 1n_l/mi_nute)
`
`' severe liver parelieliyinal damage
`
`° jaundice
`
`0 existing severe bone n1:i_trow depression and severe blood count :ii'JI'l0l'I'i1'.1_lfii:it‘5i
`
`- major surgery less than 30 days before stellting tlierapy
`
`- infe¢:tions,espeei;1lly associated with leukopenia (risk of generalization oFinfeetion)_
`
`2.6
`
`Type of use
`Ribo1i1ustin‘“ is administered as 21 shott intravenous inftlsion over 30 to 60 minutes
`
`after reconstitution in }1(.'.COI‘dal1CI? with the instructions.
`
`The ready—to—use solution is prepared as follows:
`
`Dissolve the CDI‘l'CI.‘fl1tS oF one Rilion'1ustjn" vial with piereeable stopper containing
`
`35 IJ1gl\C11L‘l;.I.IT1LlSti11E‘ in 10 ml by shalcjng.
`
`Dissolve the contents of one R.ibonu1stin"" vial with pierceable stopper containing
`
`100 mg bendanmstine in 40 ml by shaking.
`
`As soon -as -.1 clear solution is obtained (this L1SLl:1lly takes 5 to 10 minutes). dilute the total
`
`dose of Riliomustin‘ immediately with 0.9 00 NaCl solution to produee :1 final volume of
`about 5'0!) ml.
`
`IO
`
`FRESENIUS KABI 1005-0008
`
`

`
`2.7 Dosage by individual and daily doses
`Benelaintlstine is administered as monotlierapy or in combination with other chemothera-
`
`peutic agents in :1 variety of dosages and regin1e1is.'I‘liere 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 filrtlier dosages and regimens please refer to the
`
`Iliedieal literature; illioriiiatiozi is also available on request.
`
`Treatment should be terminated if the leukocyte and/or platelet count has decreased to
`
`levels 5 3,000/pl and 5 75,000/p,l respectively.
`
`Ribo1nustin"" treatment can be continued after the leukocyte count has increased to 2.
`
`4,00!)/til and the platelet count to 2 l(l0,l'i00/ttl.
`
`'l"l1e portion of Free bendarnustine liyclroeliloricle may be increased by up to 30% if the level
`
`ofalbuniin in plasma is very low (5 30 g/l).A dose reduction may therefore be consicleretl
`
`in such eases. Examples of different dosages and regimens (depending on the iiiclication):
`
`Htidgleirifc cifserise isrciges {I-115}
`
`“DBflBg'_ r§gi111et1"'
`
`daunorubit;in
`
`25 nig/tn”
`
`on days 1-i-15
`
`bleoniyein
`
`Vineristine
`
`I0 nrg/nr‘
`
`on days 1+ 15
`
`1.4 mg/ 111"
`
`on days l+l5
`
`Ribon1ustin""
`
`50 nig/In”
`
`on days I— 5
`
`repetition oftlie cycle aFte1' -1 weeks.
`
`Nflfi-Hfltigkiiii ly:-iiplitumi
`
`“BOP regri1r1en":
`
`Ribornusti11""
`
`60 mg/m’
`
`on days 1-5
`
`viireristiiie
`
`2 irig/n1"
`
`on Clay '1
`
`preclnisone
`
`100 mg/n1"
`
`on days l~5
`
`repetition oftlie cycle afier 3 weeks.
`
`l’iasrrmtyttirm:
`
`“BP regimen":
`
`Ribomustin""
`
`120-150 mg/ 111" on days 1+2
`
`prednisone
`
`60 trig/in“
`
`on days 1+4
`
`repetition ofitlie cycle after 4 weeks.
`
`Ciiitii-tit lyriipi-mtytit leuieetrifrt
`
`Ril'iomusti11""
`
`80— l 00 mg/ 111-’
`
`on days 1+2
`
`repetition of the Cycle after 4 weeks.
`
`Breast tamer
`
`“BMF regimen":
`
`Ribou1i.1stin""
`
`I20 mg/or‘
`
`on days 1+8
`
`liietliotrexate
`
`40 Irlg/In-'
`
`on days 1+8
`
`5—fluorouaci.l
`
`600 irig/in"
`
`on days 1+8
`
`repetition of the cycle after 4 weeks.
`
`“Seeom'.l line therapv”:
`
`Ribor11ustin“"
`
`100-150 nlg/I113 on days I-I-2
`
`repetition of the cycle after 4 weeks.
`
`Note:
`
`No dose reeomrnenelatious can currently’ lie given for ehild1'en,since there is no experience
`
`with this age group.
`
`111
`
`FRESENIUS KABI 1005-0009
`
`

`
`Toxicology
`
`3.1 Acute toxicity
`The LDW in mice afier intravenous and intraperitoneal administration is
`
`80 mg/kg body weigl'1t.The 1.135,. in rats after intravenous adniinistration
`
`is 40 ing/kgbody weight (62).
`
`3.2 Subchronic toxicity
`Bendarnustine hydrochloride was administered orally to rats in dosages of 10,
`
`'20, 40, 80 and 160 mg/kg daily over a period of28 darys.Tl:te substance was
`
`not lethal up to a dose of 40 mg/kg. I-iematologic and non-hematologic side
`
`effects were slight to moderate and reversible after treatment termination.Tl1e
`
`LDEU was reached at dosages of 2 80 rng/kg daily.
`
`In dosages of 80 and 16fl nrg/kg bendatzuustine induced bone marrow aplasia,
`
`atrophy oflymphatic tissue and liistopathologie abnormalities of the kidneys
`
`and intestine.'I'herc was no evidence of damage to other organs (33).
`
`Subclironic 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 ofappe-
`
`tite. During the recovery phase evacuation ofliquid stool and behaviourzt]
`
`changes were observed. Gross examination revealed rnucosal liypet-ernia and
`
`intestinal lreniorrhagic zones in these animals. Microscopic analysis also revea-
`
`led pronounced changes to lymphatic tissue as an indicator of inimuno—
`
`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 wei§it loss, dose-dependent leukocyte
`
`suppression) (I1).
`
`11
`
`FRESENIUS KABI 1005-0010
`
`

`
`3.3 Mutagenic and carcinogenic effects
`Bcndalmistinc induces chromosome aberrations and exhibits mutagcnic activity in cell
`
`culture: and allimal models (9.2: 54; 55).
`
`Lung tumours and mammary carczinomas were detected in tnicc after administration of
`
`1)€l‘1daI1‘lL15til‘l(E.‘
`
`(15).
`
`3.4 Reproductive toxicity and teratogenic activity
`B{t1]d:1.l1'l1.15t1I1C was cmbryotoxic and tazratogcnic in pregnant mice (24).
`
`FRESENIUS KABI 1005-0011
`
`

`
`Pharmacology
`
`4.1 Efficacy in animal models and cell -culture
`Schnabel et al. (62) demonstrated with three experimental inurine tumours
`
`(leukemia I.A_]l , sarcoma 180, Ehrlich ascites carcinoma) that bendamustine is
`
`comparable to cyclophosphamide in its suppressive eflect on tumour growth-
`
`FuIther studies (14) have evaluated the antineoplastic activity of bendaniustine
`
`in 8 experimental mutine tumour models using different transplantation tech-
`
`niques and forms of administration. Bendamustine exhibited a suppressive
`
`effect on tumour growth for 6 turnouts (Ehrlich ascites carcinoma, leukemia
`
`L1210, leukemia P3 88, melanoma B16, Lewis lung carcinoma and lymphoma
`
`ABDtfi) (4).
`
`Strumberg et al. (66) studied the cytotoxic eEFect ofbenclaniustine on human
`
`ovarian and Inaniniaty 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—
`
`phosphan1ide,rnelphalan and cannnstine).
`
`Schwaenen et al. (65) studied the in vitro induction of apoptosis in l3~CLl..
`
`cell lines by bendainustine and fludarabine alone and in combination. Benda-
`
`inustine showed dose-1-elated apoptosis induction of 8% to 94% after 48 hours.
`
`13
`
`FRESENIUS KABl 1005-0012
`
`

`
`In 10 of 12 B—CLL cell lines the combination of bendaniustine and lzludal-abine resulted
`
`in a sylicrgistic effect afier 48 hours, i.e. a 14-fold higher apoptosis rate than expected
`
`(see Figure 2).
`100*-
`
`- fludarabine 0.7 ngiml
`I bendamustine 2 ngrml
`8 expected
`I combination
`
`95,99
`+3
`$88.42
`
`
`
`
`fig :
`
`3 so —
`'3
`
`40 -—-
`
`E §
`
`zn —
`
`0
`
`24 I1
`
`43 11
`time
`
`?'2 h
`
`Figure 2: En hanced apoptosis of B—CLL lymphocytes on incubation with bendamustine 2‘ fludarablne (accor~
`cling to Schwaenen et aI.)
`
`Chow et al. (12) studied the in vim: induction ofapoptosis and inhibition of proliferation of
`
`neoplastic cells in low—g1-ade I"~U~lI_ using combinations ofestablished cytotoxic drugs with
`bendarr1ustine.Tl1e combination oi‘lienda1nL1stine with elaclribine resulted in additive or
`
`even synergistic effects on -apoprosis and inhibition of cell proliferation on all tested cell
`
`populations (DOI'Il'1—2;WSU—Ni"iI.; ex vivo cells ofpatients with C[.I.,le11kemic low—
`
`grade B—NI‘lI.,T-N1-lI.). In contrast, the combination ofbendalnustine with either doxoru-
`
`bicin or mitoxantrone showed i=ll'1t‘:lgD1li§!'.iC effects both on apoptosis and inhibition ofcell
`
`proliferation (Figure 3).
`
`Combination index of tested drug combinations
`
`15 —
`
`5 0 —
`
`CI
`
`
`
`Antagonism
`Ci:-v'i
`
`synergism
`Cici
`
`
`
`14!
`
`B1-D
`
`E+M
`
`B-i-C
`
`Figure 3: Combination index {Cl} for apoptosis {A} and inhibition of proliferation {P}.
`Drug combinations;
`B+ B: bendarnustme + doxorubiclun.
`3+ M: ben da mustine + rnitoxan Krone.
`8+ C. ben darn ustine + cladribine
`
`FRESENIUS KABI 1005-0013
`
`

`
`Bendamustiiie induced apoptosis was p53 independent, thus the ;1pO[JtOS‘iS cascade seems
`
`not to be influenced by belidtunustine.Therefore, the expression patterns ot‘the drug com-
`
`hin:n:ions containing heiidaniustiiie depended on the expression caused by the coinhination
`
`partner (Ci0:'{O1'1.li)'iCiI'1. niitoxzmti-one or el‘.1drihine).
`
`This cell model demonstrated that hendainustiiie has '.1 different mecha_nisn1 ofinter-.1ction
`
`than that ofpurine aiiulogs and a different nianner of induction of il'pO[Jl:05iS than alcylating
`
`agents.
`
`These results stlggest that schedules using eon"il)ir1ations ofbendamustiiie and ;u1tI1rac}-'-
`
`elines should not be reconii-nendcd For the treatrnent of'low~gr:u:ie N] 11., \Vi"1I.?l‘L?'Ji!‘- benda-
`
`inustine combined with cladribine could be considered for the development of Future
`
`l'I't"2ll‘l'1'lEDt St 1'3 [Cgi€5.
`
`Schleucher et al. (61) studied the i.l1tt‘r“.1CtiOT1 ofbeiidaintrsrine with vinorelhine, 5—FU and
`
`paclitaxel in cytotoxicity assays. In addition, he studied whether the efficiency is influeiiced
`
`by the sequence ofthe drugs.
`
`I3e11danu.1stine showed signific;-int cytotoxicity in human t1.1IT10I.l1‘ eel} Iines. even in those
`
`with MDl{~1 :ictivity. The sequence ofbendamustine anal 5-FU showed additive to syner-
`
`gistic inter.1ctions. Bendamltstine and vinorelbine showed a sequence dependent synergism
`
`in 2 difterent cell 1i11es.’l‘he cytotoxic activity of'pscIit3xeI lnay be iiicreased in combinati-
`on with bend;i1ni1stine.
`
`Interactions of the cytotoxic agents bendamustine. 5-FU. paclitaxel, and vinorelbine
`
`on breast cancer cell lines MCF-7 (wild type) and MDA-MB231°
` benclaniustine before 5—FU
`synergistic
`
`additive 5—FU before bL“I]d:i.l1‘l1.lStiI1t.‘
` MDA—MB23}
`
`bendamustine before :3—FU
`synergistic
`5~1"-U before bend-.i1nustine
`mtagonistic
`
`
`
`
`MCF-7
`
`bendamiistine before petclitaxel
`
`MB23 1
`
`hendaniustiiie before p.'1Ci_it3_‘{Ei
`
`ptttzlitastel before bendarnustine
`
`p:iclit-axe] before beiidarmlstiiie
`
`MCF—7
`bendmiustinc before vinorelbine
`
`vinorelhine before bendarnustine
`
`MDA—MB231
`
`bendsmustine before vinoreibine
`
`vinorelbine before bendarnustine
`
`synergistic
`
`Lmtagonistic
`
`aiitagoiiistic
`
`synergistic
`
`synergistic
`
`
`
`synergistic
`
`synergistic
`
`synergistic
`
`“ incubations with bendamustine, paclltaxel, and vinorelbine for 2 h, with 5—FU for 24 h
`
`15
`
`FRESENIUS KABI 1005-0014
`
`

`
`4.2 Mechanism of action
`
`Bendamustinc is a bifunctional alkylating agent with antineoplastic and eytociclal properties
`
`(Figure 4).
`
`benzimiclazole ring:
`
`purine analogue alkaneearboxylic acid:
`
`
`N~mustard—group:
`provides water-solubility
`alkylating agent
`
`(reduced toxicity due
`
` to electron affinity)
`
`Figure 4: Chemical-functional structure of bendamustine
`
`The efficacy is attributable mainly to crosslinking of the DNA single and double strands by
`
`a.lky1ation.This produces a disturbance of the matrix function of DNA and DNA synthesis.
`
`There is also crosslinkjng between DNA and proteins and between proteins thernselves.
`
`It is not yet known whether the benzimidazole ring possesses additional antimetabolite pro—
`
`per-ties (18; 30; 66; 68).
`
`16
`
`FRESENIUS KABI 1005-0015
`
`

`
` 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.
`
`FRESENIUS KABI 1005-0016
`
`

`
`5.7
`
`Biological half-—life
`Following i. V. bolus injection of bendaniustine in the usual therapeutic dosages, the plasina
`
`level in man follows a biphasie exponential patteriiflihe elimination liaifliiiie two: is bet-
`
`ween 6 and ii) n1inutes,:md the terminal elimination half-life t,,3B between 38 and 36
`
`minutes. After i. V.1it'lJ1'l‘ll1iStI'atiOI1 in several studies the central volume of distribution was
`
`between 8.6 and ll.2 l. Under steady state COI'.l(‘liti0I15 the volume of distribution was
`
`15.8 * 30.51(4l;42).
`
`5.8
`
`Elimination
`
`Elimination is rapid, bipliasie and pretioziiitiaiitly ren3.l.Me;1n total elear.1nee was calculated
`
`as 528.‘) - 826.2 ml/ininuteflilie Following Fractions, referred to the total amount of admi-
`
`nistered parent compound, were detected in urine: bendarnustine 45.3%.l1ydroXy-benda-
`
`n1I.Istii1e 2-3.8%, an unidentifiecl polar metabolite 13.4%, l_’s—hyclro:cy—bendainustine 8%, an
`
`unidentified apolar metabolite 5.1% and N-deInetliyl—bendainustine 1.5%. Mainly polar
`
`metabolites are eliminated by the biliary route (41; 43).
`
`5.9
`
`Elimination in impaired renal function
`Beiiclainnstine is predominantly eliminated by the renal route.Tl1e drug should
`
`not be given to patients with impaired renal function (glonienflar filtiatioli rate
`
`< 30 ml/minute).
`
`5.10
`
`Elimination in impaired hepatic function
`Bendaimlstine is Ineolbolized in the liver and eliminated to 3. small extent (inainly polar
`
`metabolites) via the biliary systeIn.The drug should not be given to patients with severe
`
`hepatic parenchymal damage and jaunclice.
`
`5.11
`
`Dialysability
`It is not yet known whether bendalnustine or its metabolites are di;Llyzable.
`
`13
`
`FRESENIUS KABI 1005-0017
`
`

`
`5.12 Metabolism
`
`Bmdamustinc: is ITlt.‘.tabOTiZ{.“£.'T mainly in the 1ivcr.'1'hc main biotransfortnation product is a
`
`cytotoxic hydroxy derivative (I5-hydroxgrbmdamustin c), which is formed by hydroxylation
`of the b11t:111oic acid side cl1ain.This substance shows elimiilation kinetics similar to those
`
`ofthr: pzlrcnr compound (tug about 19 minutnzs). In the dose range: 0.5-5.0 mg/kg, clearan-
`
`cc and the AUC (Ii-OI I—b::ndamu5ti11c) /'AUC (bendzlmtlstine) ratio are nomdost: dcpcnw
`
`dent.FI.1rthe-t ide11tified metabolites are 1110nohydr0:cybe11da111ustine,dihyd1'oxybe11dz|mL1sti—
`
`ms, hydroxy—B—l1ydroxybcndamL1stinr3 and N—dcmcrtluylbcndamustine (41; 42; 48) (Figure 5).
`
`C|CH.(IH.~.,‘_‘
`
`>—CH,CH.»CH:COUH
`
`}lDCH.Cil...,‘
`
`ClCH.CH,/N N
`T
`CH.
`Gil-hem-Iamustine
`
`>-—CH,CH,CH,CUOH
`
`'""'*am"“'"P
`
`T/ cm \
`
`
`
`0HCHaCHa-..__
`UHCHKHI/N
`
`C|CH:CH:~..\N
`CIcH,cH,/
`
`N
`
`%CH;CHyCH;CO0H
`
`TH
`N-demelhylhendanlmllne
`
`N
`
`>—CH,CH,CHyCUOH
`
`T
`I
`E"
`di-ml-hendamustine
`
`
`
`{T}
`pol rrnmholrt
`pol; nmaboln: nu
`apolal meIaho1|u- HIT)
`
`ClCH.CH,\
`
`cm-I.t:H,/N
`
`>—CH:CHI‘.}HCH,CDC|H
`
`N
`T
`CH;
`B~0H~|n-ndarnustlne
`
`HOCH.~CHn.,,~
`crcmcu,/N
`
`N
`
`>—l'.Hy(HOHCH¢CO0H
`
`T
`C"*
`r_IHvfi-OH~he|u.larnustlnu
`
`Figure 5: Metabolism of bendamustine (act. to Preiss et all.)
`
`19
`
`FRESENIUS KABI 1005-0018
`
`

`
`Clinical efficacy
`
`6.1 Hodgkin's disease (stage ||~|V)
`Initial research findings have shown that bendamustine is at least as effective as cyclo-
`
`phosphamide (3).
`
`In 3 Further prospective randomized study; I-Itiche ct co-workers (31) compared various
`
`chemotherapy protocols in 73 evaluable patients with Hot_lg1<in’s disease stage IIIB or
`
`IV (Ann Arbor classif1cal:ion).O11ly patients with ptiinary or secondary resistance to the
`
`(IVPP regimen (cyclophospharnide / vinblastine / procatbazitie / pt-ednisone) were
`
`enrolled in the study. One treatment Cycle lasted 28 days, and day 16 to day 28 were
`treatment-fi-ee.
`
`Treatment regimens
`
`pave (n = 38)
`
`
`
`D-aunorubicin
`25 mg/mi i.v. on days 1 + 15
` Bleoniycin
`
`Vincristinc
`1.4 mg/tn’ i.\;. on days 1 + 15
`
`Bendamustine
`50 mg i.v. on days 1 — S
`
`
`
`10 mg/m-’ i.v. on days 1 + 15
`
`ABVD (n = 35)
`
`Doxorubicin
`
`Bleornycin
`
`Vincristine
`
`Dacarbazine
`
`
`
`Study results
`
`25 mg/In‘ i.v. on days 1 + 15
`
`10 mg/m3 i.v. on days 1 + 15
`
`1.4 mg/m’-' i.v. on days 1 + 15
`
`150 mg/n1’ i.v. on days 1 — 5
`
`Number of
`patients
`
`CR
`n W»)
`
`'
`
`CR + PR
`n (36)
`
`Median
`remission
`duration
`(months)
`
`Median
`survival
`
`{rn.onth5)
`we
`
`new
`we
`
`20
`
`us
`
`FRESENIUS KABl 1005-0019
`
`

`
`Co11elusio11s:The combination tlierapy eolitainixig l.'>CI'1Ll€LI'I‘lI_'l5itil'1E
`
`is equiv:1lent in effective-
`
`ness to the reference therapy but is better tolerated.
`
`Herold et al. (35) evziltiated the efficacy ot‘cy<.‘lic alternating cliernothempy in the therapy
`
`ofpatients with non—pretreated advanced llodgkirfs disease (stage IIIA, lllB, IVA, IVB)
`
`in at multicentre T;1t]t‘l(‘lI‘l'LiZt"C.l study.
`
`Treatment regimens
`CVPP (n = 40)*
`
`Cyelophosplianlide
`
`Vinblastine
`
`Procarhazitie
`
`Prednisoloiie
`
`
`
`600 mg/m'’ i.v. on days I + 8
`
`6 mg/111*‘ i.v. on days 1 + 8
`
`100 mg oral on days 1 — 14
`
`4-0 Ing/mi oral on days 1 * I4
`
`DBVB — alternating with the above CVPP regimen (n = 40)”
`
`Datlllorubiciil
`
`Bleomycin
`
`Vincristine
`
`Bendaniustine
`
`
`
`25 mg/mi i.v. on days 1 + T5
`
`10 111g/m-' i.n1. on days I + 15
`
`2 mg i.v. on days 1 + 15
`
`30 mg/m3 i.v. on days I ~ 5
`
`treatrnent—free interval clay 15 to day 28; prednisolone only in cycles 1 and 4
`"
`** treatment-free interval day 15 to day 28
`
`The results of this treatinelit demonstrate that the two therapeutic regimens -are equally
`
`effective. No statistically significzmt dif‘ferences were detectable.
`
`Study results
`Number of
`
`patients
`
`
`
`No
`remission
`
`DBVB — alternating with the above CVPP regimen
` 23615)
`
`With the aim of reducing the risk oflste cmiiplieations of combined radioehemotherapy
`
`in patients with non-pretreated Ilodgkinis disease and ofminimizing risk factors, Herold
`
`et al. (26; 37) studied the efficacy of reduced 1-adio~'.1nd clieliiothempy as sandwich tl1e1-apy‘.
`
`The followzing pararneters were regarded as partictlletr risks: large mediasri_n'.1.l tumour,
`
`B—svmptoms, extensive abdominal involvement. extranodal involvement — especially of
`
`the lungs ~_.L1nfavourahle histologic subtypes — especially lymphocyte-depleted histologic
`
`subtypes -, increase in SE'CliI1‘1E.'I'll:;1tiDl1 rate of more than 50 mm in the E1-st hour.
`
`The therapeutic regimen developed in the pilot study is shown below.
`
`FRESENIUS KABI 1005-0020
`
`

`
`Therapeutic regimen
`CVPP!ABVCy hybrid regimen
`
`Cyclopliospliarnide
`
`600 mg/n1" i.v. on day 1
`
`Vinhlastine
`
`Procarbazine
`
`Prednisolone
`
`Doxoruhicin
`
`Bleornycin
`
`Vincristine
`
`6 mg/mi i.v. on day 1
`
`100 mg/ I'I1‘] oral on days 1 —— 7
`
`40 mg/ n11 oral on days 1 - 14
`
`E5 mg/In" i.v. on day 8
`
`15 mg/m1i.m. on day 8
`
`2 1'ngi.v. on day 8
`
`Bendaannstine
`
`30 mg/In" i.v. on days 8 — 13
`
`Treatnient—fi-ee interval day 15 to day 33; repetition day '29
`
`Radiotherapy was administered with -.1 reduced fiical dose of‘35 Cy as involved field
`
`irradiation, and chemotherapy comprised six cycles.
`
`[11 addition to the favourable results in terms ofreinjssioii rate (81% patients with CR, 13%
`
`with PR and only 7% non—responders) the Ehvear survival data ofthe pilot study are signi-
`ficant.
`
`After :1 median observation period oF108 months, 27 oI"35 patients are in their first com-
`
`plete remission. Eight patients relapsed (after 14, 30, 30, 31,36, 38, 48 and 77 months).
`
`Renewed complete remission could be achieved in 3 oiithese 8 patients by salvage therapy.
`
`The proportion of patients classifiable as responders (= rate of Freedom from therapeutic
`
`fililure) was 78% (after 5 years) and 70% (after 9 ve31‘s).Total survival after 5 and 9 years was
`
`83% and 73% respectively.
`
`In a subsequent phase II! study (28), I00 non~pretreated patients were treated with either
`
`cyclophosphamidc or bendamustine, each combined with vinhlastine. procarhazine,predJ1i—
`
`solone. doxoruhicin, vincristine and hleoniycin and also received radiotherapy. The results
`
`of the above pilot study were confirmed. Comparable remission and survival rates were
`
`determined For both therapeutic rcgimcn5.The CR rate was 88% in the hendamustine
`
`group and 81% in the eyclophosphamide group. The 5-year total survival rate at interim
`
`analysis (68 months follow-up) was 83% and 80% respectively (bendamustine and cyclo-
`
`phosphamidc group)-
`
`6.2 Non-Hodgkin lymphoma (NHL)
`
`5.2.1 Indolent lymphoma
`Ruflfert et al. (56) studied the efficacy ofhendamustine in combination with vincristine
`
`and prednisolone (BOP) in 31 patients with refractory. progressive, lnalignant N1-LL (see
`
`tahie).
`
`FRESENIUS KABI 1005-0021
`
`

`
`Patient characteristics
`
`Stages
`[11 A / [[1 B
`
`IV A I {V B
`
`1]
`
`20
`
`Histology according to Kiel classification
`
`10
`
`I?
`
`9
`
`9
`23
`
`15
`
`
`
`Low grade
`
`Intermediate grade
`
`High grade
`Previous treatment
`
`Knospe
`COP
`
`CHOP—Bleo
`
`Relapse rate
`
`
`
`
`
`1" relapse
`
`2"‘ relapse
`
`3"‘ relapse
`
`Treatment regimen
`Cl1E'11‘1Utl1€I‘21py‘ was given according to the following regimen (repetition day 32 :
`
`Belldanlustine
`
`Vincristine
`
`Prednisolone
`
`
`
`60 1Tlg/I112 i.v. as :1 short infiision over 1 hour on days I r 5
`
`or 100 mg/n13 i.v. on days 1 — 3
`
`1.4 mg/m-' i.v. on day 1 (up to n'1:Lx. 2 mg)
`
`100 nig/in’ i.v. on clays I — 5
`
`The study results conclusively show the efteetiveiiess of the treatment regimen as a second-
`
`line or tlLird—lj.ne tlierapy in patients with Knospe, GOP and CI-IC)P—Bleo refiactory nmlig—
`nzmt NHL.
`
`Study results
`Number of
`patients
`
`
`
`
`
`PD
`I1 (Va)
`
`The patients with complete remission showed 21 reinission duration of 5 to 34+ months
`
`(niedian 12.4 montlis) and patients with PR. showed Pl remission dumtion of 1 to 1‘) montlis
`
`(lnedian 9.8 1nontl1s).Tl1e total survival rate was 68% for the ohset-vation period. Malignant
`
`NHL was only in 13% of the patients the cause ofeleath.
`
`23
`
`FRESENIUS KABI 1005-0022
`
`

`
`Evaluation ofthe study results taking into account the nialignancy-grade showed that
`
`riltliough no complete remissions were acliieved for low—grade Ni IL, all patients achieved
`
`partial 1-eniission.The reniission duration was between 3 and 19 months.
`
`Six and