Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
APPROVED PROFESSIONAL INFORMATION FOR BENDAHET 25 & 100  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
BENDAHET 25 (powder for concentrate for solution for infusion)  
BENDAHET 100 (powder for concentrate solution for infusion)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
BENDAHET 25: Each 10 mL vial contains 25 mg bendamustine hydrochloride.  
BENDAHET 100: Each 20 mL vial contains 100 mg bendamustine hydrochloride.  
1 mL of the concentrate contains 5 mg bendamustine hydrochloride of when reconstituted according to  
Posology and method of administration instructions.  
BENDAHET 25: Contains sugar – mannitol (42.50 mg)  
BENDAHET 100: Contains sugar – mannitol (170 mg)  
For the full list of excipients, see section 6.1  
April 2024  
Initials…MU…….  
Page 1 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
3 PHARMACEUTICAL FORM  
BENDAHET 25: White to off-white lyophilised powder.  
BENDAHET 100: White to off-white lyophilised powder.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
BENDAHET is indicated for the following conditions:  
•
•
•
•
First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom  
fludarabine combination chemotherapy is not appropriate.  
First-line treatment of indolent CD 20 positive non-Hodgkin’s lymphoma in combination with  
rituximab  
Indolent non-Hodgkin’s lymphomas as monotherapy in patients, who have progressed during or  
within 6 months following treatment with rituximab or a rituximab containing regimen.  
Front line treatment of multiple myeloma (Durie-Salmon stage II with progress or stage III) in  
combination with prednisone for patients older than 65 years who are not eligible for autologous  
stem cell transplantation and who have clinical neuropathy at time of diagnosis precluding the  
use of thalidomide or bortezomib containing treatment.  
4.2 Posology and method of administration  
Posology  
Monotherapy for chronic lymphocytic leukaemia  
100 mg/m2 body surface area BENDAHET on days 1 and 2; every 4 weeks.  
April 2024  
Initials…MU…….  
Page 2 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Combination treatment for first-line indolent non-Hodgkin’s lymphoma  
90 mg/m2 surface area BENDAHET on days 1 and 2 in combination with 375 mg/m2 body surface area  
rituximab as a slow i.v. infusion on day 1; every 4 weeks.  
Monotherapy for indolent non-Hodgkin's lymphomas refractory to rituximab  
120 mg/m2 body surface area BENDAHET on days 1 and 2; every 3 weeks.  
Multiple Myeloma  
120 – 150 mg/m2 body surface area BENDAHET on days 1 and 2, 60 mg/m2 body surface area  
prednisone intravenous or orally on days 1 to 4; every 4 weeks.  
Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to ≤ 3 x 109/L  
or ≤ 75 x 109/L, respectively. Treatment can be continued after leukocyte values have increased to  
> 4 x 109/L and platelet values to > 100 x 109/L.  
The leukocyte and platelet Nadir is reached, after 14 – 20 days with regeneration after 3 – 5 weeks.  
During therapy free intervals strict monitoring of the blood count is recommended (see section 4.4).  
In case of non-haematological toxicity dose reductions have to be based on the worst CTC (common  
toxicity scale) grades in the preceding cycle. A 50 % dose reduction is recommended in case of CTC  
grade 3 toxicity. An interruption of treatment is recommended in case of CTC grade 4 toxicity.  
April 2024  
Initials…MU…….  
Page 3 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
If a patient requires a dose modification the individually calculated reduced dose must be given on  
day 1 and 2 of the respective treatment cycle.  
Special populations  
Elderly patients  
There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).  
Renal impairment  
On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with a creatinine  
clearance of > 10 mL/min. Experience in patients with severe renal impairment is limited.  
Hepatic impairment  
On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic  
impairment [serum bilirubin < 2 mg/dL (34,2 μmol/L)].  
A 30 % dose reduction is recommended in patients with moderate hepatic impairment (serum  
bilirubin [2 - 3,0 mg/dL (34,2 μmol/L - 51,3 μmol/L)].  
No data is available in patients with severe hepatic impairment [serum bilirubin values of > 3,0 mg/dL  
(51,3 μmol/L)].  
April 2024  
Initials…MU…….  
Page 4 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Paediatric population  
There is no experience in children and adolescents with BENDAHET  
Method of administration  
Precautions to be taken before manipulating or handing medicine  
When handling BENDAHET, inhalation, skin contact or contact with mucous membranes should be  
avoided (wear gloves and protective clothes). Contaminated body parts should be carefully rinsed  
with water and soap; the eye should be rinsed with physiological saline solution. If possible, it is  
recommended to work on special safety workbenches (laminar flow) with liquid impermeable,  
absorbing disposable foil. Pregnant personnel should be excluded from handling cytostatics.  
For instructions on reconstitution of the medicine (see section 6.6).  
BENDAHET is administered by intravenous infusion over 30 – 60 min.  
Infusion must be administered under the supervision of a physician qualified and experienced in the  
use of chemotherapeutic agents.  
Poor bone marrow function is related to increased chemotherapy-induced haematological toxicity.  
Treatment should not be started if leukocyte and/or platelet values dropped to < 3 x 109/L or < 75 x  
109/L, respectively (see section 4.3).  
4.3 Contraindications  
April 2024  
Initials…MU…….  
Page 5 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
•
•
Hypersensitivity to bendamustine or any of the excipients in BENDAHET.  
Pregnancy and lactation.  
•
•
•
Severe hepatic impairment [serum bilirubin > 2,0 mg/dL (34,2 μmol/L)].  
Jaundice  
Severe bone marrow suppression and severe blood count alterations (leukocyte and/or  
platelet values dropped to < 3 x 109/L or < 75 x 109/L, respectively).  
•
•
Major surgery less than 30 days before the start of treatment.  
Infections, especially involving leukocytopenia.  
•
•
•
Yellow fever vaccination or any other live (attenuated) vaccination  
Congenital QT prolongation  
Concomitant medicines causing QT prolongation.  
4.4 Special warnings and precautions for use  
Myelosuppression  
Patients treated with bendamustine hydrochloride experience myelosuppression. Treatment-related  
myelosuppression, leukocytes, platelets, haemoglobin, and neutrophils must be monitored at least  
weekly. Prior to the initiation of the next cycle of therapy, the following parameters are recommended:  
Leukocyte and/or platelet values > 4 x 109/L or > 100 x 109/L, respectively.  
Infections  
April 2024  
Initials…MU…….  
Page 6 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Serious infection, including pneumonia and sepsis, has been reported with bendamustine  
hydrochloride. Infection has been associated with hospitalisation, septic shock and death. Patients with  
neutropenia and/or lymphopenia following treatment with bendamustine hydrochloride are more  
susceptible to opportunistic infections. Opportunistic infection such as Pneumocystis jirovecii  
pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV) have been reported.  
Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (< 600/μl) and low  
CD4-positive T-cell (T-helper cell) counts (< 200/μl) for at least 7–9 months after the completion of  
treatment. Lymphocytopenia and CD4-positive T-cell depletion is more pronounced when  
bendamustine is combined with rituximab. In case of low CD4-positive T-cell counts (< 200/μl)  
Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered. Cases of tuberculosis have  
been less frequently reported compared to other infections. Latent or dormant tuberculosis may become  
active. (see section 4.8)  
Patients with myelosuppression following BENDAHET treatment should be advised to contact a  
medical practitioner if they have symptoms or signs of infection, including fever or respiratory symptoms.  
Discontinuation of bendamustine hydrochloride should be considered if there are signs of opportunistic  
infections. The presence of tuberculosis should be excluded before treatment with BENDAHET is  
commenced.  
Skin reactions  
A number of skin reactions have been reported. These events have included rash, severe cutaneous  
reactions and bullous exanthema. Cases of Stevens – Johnson syndrome (SJS), Toxic Epidermal  
Necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), some fatal,  
have been reported with the use of bendamustine hydrochloride. (see section 4.8).  
Patients should be advised of the signs and symptoms of these reactions by their prescribers and  
should be told to seek medical attention immediately if they develop these symptoms. Some of these  
April 2024  
Initials…MU…….  
Page 7 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
events occurred when bendamustine hydrochloride was given in combination with other anticancer  
agents. Where skin reactions occur, they may be progressive and increase in severity with further  
treatment. If skin reactions are progressive, BENDAHET should be withheld or discontinued. For severe  
skin reactions where a relationship to BENDAHET is suspected, treatment should be discontinued.  
Cardiac disorders  
During treatment with BENDAHET the concentration of potassium in the blood of cardiac patients must  
be closely monitored. When serum potassium levels are < 3,5 mEq/L, an ECG measurement must be  
performed, and potassium supplement must be given. Fatal cases of myocardial infarction and cardiac  
failure have been reported with bendamustine hydrochloride treatment. Patients with concurrent or  
history of cardiac disease should be observed closely.  
Nausea, vomiting  
An antiemetic should be given for the symptomatic treatment of nausea and vomiting.  
Tumour lysis syndrome  
Tumour lysis syndrome associated with bendamustine hydrochloride treatment has been reported in  
patients in clinical trials. The onset tends to be within 48 hours of the first dose of bendamustine  
hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures  
include adequate volume status and close monitoring of blood chemistry, particularly potassium and  
uric acid levels. The use of allopurinol during the first one to two weeks of BENDAHET therapy can be  
considered. However, there have been a few cases of Stevens-Johnson Syndrome and Toxic  
Epidermal Necrolysis reported when bendamustine hydrochloride and allopurinol are administered  
concomitantly.  
April 2024  
Initials…MU…….  
Page 8 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Anaphylaxis  
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms  
are generally mild and include fever, chills, pruritus and rash. Severe anaphylactic and anaphylactoid  
reactions have occurred. Patients must be asked about symptoms suggestive of infusion reactions after  
their first cycle of therapy.  
Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids must  
be considered in subsequent cycles in patients who have previously experienced infusion reactions. In  
patients who experienced Grade 3 or worse allergic-type reactions, BENDAHET should be  
discontinued.  
Contraception  
Bendamustine hydrochloride is teratogenic and mutagenic. Women should not become pregnant during  
treatment. Male patients should not father a child during and up to 6 months after treatment. They  
should seek advice about sperm conservation prior to treatment with BENDAHET because of possible  
irreversible infertility.  
Extravasation  
An extravasal injection should be stopped immediately. The needle should be removed after a short  
aspiration. Thereafter the affected area of tissue should be cooled. The arm should be elevated.  
Additional treatments like the use of corticosteroids are not of clear benefit. There have been reports of  
necrosis after accidental extra-vascular administration and toxic epidermal necrosis, tumour lysis  
syndrome, and anaphylaxis (see section 4.8).  
April 2024  
Initials…MU…….  
Page 9 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Other malignancies  
There have been reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative  
disorders, acute myeloid leukaemia and bronchial carcinoma.  
4.5 Interaction with other medicines and other forms of interaction  
No in vivo interaction studies have been performed.  
When BENDAHET is combined with myelosuppressive agents, the effect of BENDAHET and/or the  
co-administered medicinal products on the bone marrow may be potentiated. Any treatment reducing  
the patient's performance status or impairing bone marrow function can increase the toxicity of  
BENDAHET.  
Combination of BENDAHET with ciclosporin or tacrolimus may result in excessive immunosuppression  
with risk of lymphoproliferation.  
Cytostatics can reduce antibody formation following live-virus vaccination and increase the risk of  
infection which may lead to fatal outcome. This risk is increased in subjects who are already  
immunosuppressed by their underlying disease.  
Bendamustine hydrochloride metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. Therefore,  
potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and  
cimetidine exist.  
April 2024  
Initials…MU…….  
Page 10 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
CYP1A2 inducers, such as omeprazole, can reduce exposure to bendamustine.  
4.6 Fertility, pregnancy and lactation  
Women of child-bearing potential  
Women of childbearing potential must use effective methods of contraception both before and during  
BENDAHET therapy.  
Pregnancy  
There is no adequate data from the use of BENDAHET in pregnant women. In non-clinical studies  
bendamustine hydrochloride was embryo-/foetolethal, teratogenic and genotoxic. Therefore,  
BENDAHET is contraindicated during pregnancy (see section 4.3).  
Breastfeeding  
It is not known whether bendamustine hydrochloride passes into the breast milk, therefore it  
BENDAHET is contraindicated during breastfeeding (see section 4.3). Breastfeeding must be  
discontinued during treatment with BENDAHET.  
Fertility  
April 2024  
Initials…MU…….  
Page 11 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Men being treated with BENDAHET are advised not to father a child during and for up to 6 months  
following cessation of treatment. Advice on conservation of sperm should be sought prior to treatment  
because of the possibility of irreversible infertility due to therapy with BENDAHET.  
4.7 Effects on ability to drive and use machines  
Bendamustine hydrochloride may cause side effects such as ataxia, peripheral neuropathy and  
somnolence (see section 4.8). This may influence the ability to drive and use machines. Patients should  
be advised not to drive or operate machines if they experience these effects.  
4.8 Undesirable effects  
a. Summary of the safety profile  
The most common adverse reactions with bendamustine hydrochloride are haematological adverse  
reactions (leukopenia, thrombopenia), dermatologic toxicities (allergic reactions), constitutional  
symptoms (fever), gastrointestinal symptoms (nausea, vomiting).  
b. Tabulated list of adverse reactions  
Infections and Infestations  
Frequent:  
Infection (not otherwise specified), opportunistic  
infections (including Herpes zoster,  
cytomegalovirus, hepatitis B)  
April 2024  
Initials…MU…….  
Page 12 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Less frequent:  
Septicaemia, primary atypical pneumonia,  
Pneumocystis  
iiroveci  
pneumonia,  
tuberculosis (TB)  
Neoplasm benign and malignant  
Frequent  
Tumour lysis syndrome  
Less frequent  
Myelodysplastic syndrome, acute myeloid  
leukaemia  
Blood and the lymphatic system disorders  
Frequent:  
Leukopenia  
(not  
otherwise  
specified),  
anaemia,  
thrombocytopenia,  
haemorrhage,  
neutropenia, lymphopenia, myelosuppression  
Less frequent:  
Haemolysis, Pancytopenia, bone marrow  
failure.  
Immune system disorders  
Frequent:  
Hypersensitivity (not otherwise specified)  
Less frequent:  
Anaphylactic  
reaction,  
anaphylactoid  
reaction, anaphylactic shock  
Insomnia, headache, dizziness  
Nervous system disorders  
Frequent:  
Less frequent:  
Somnolence,  
aphonia,  
dysgeusia,  
paraesthesia, peripheral sensory neuropathy,  
April 2024  
Initials…MU…….  
Page 13 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
anticholinergic  
syndrome,  
neurological  
disorders, ataxia, encephalitis  
Cardiac disorders  
Frequent:  
Cardiac dysfunction, such as palpitations, angina  
pectoris, dysrhythmia  
Less frequent:  
Pericardial effusion, tachycardia, myocardial  
infarction, cardiac failure  
Frequency unknown  
Atrial fibrillation  
Vascular disorders  
Frequent:  
Hypotension, hypertension  
Less frequent:  
Acute circulatory failure, phlebitis  
Respiratory, thoracic and mediastinal disorders  
Frequent:  
Pulmonary dysfunction  
Less frequent:  
Frequency unknown  
Pulmonary fibrosis  
Pneumonitis,  
haemorrhage  
pulmonary  
alveolar  
Hepato-biliary disorders  
Frequency unknown  
Hepatic failure  
Gastrointestinal disorders  
Frequent:  
Nausea,  
vomiting,  
diarrhoea,  
constipation,  
stomatitis, dry mouth  
April 2024  
Initials…MU…….  
Page 14 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
Less frequent:  
Haemorrhagic oesophagitis, gastrointestinal  
haemorrhage  
Skin and subcutaneous tissue disorders  
Frequent:  
Alopecia, skin disorders (not otherwise specified)  
Less frequent:  
Erythema, dermatitis, pruritus, maculopapular  
rash, hyperhidrosis  
Frequency unknown:  
Bullous exanthema, Stevens – Johnson  
syndrome, Toxic Epidermal Necrolysis (TEN),  
drug reaction with eosinophilia and systemic  
symptoms (DRESS)*  
Renal and urinary disorders  
Frequency unknown  
Renal failure  
Reproductive system and breast disorders  
Frequent:  
Amenorrhoea  
Infertility  
Less frequent:  
General disorders and administration site conditions  
Frequent:  
Mucosal inflammation, fatigue, pyrexia, pain,  
chills, dehydration, anorexia  
Multiple organ failure  
Less frequent:  
Investigations  
Frequent:  
Decrease haemoglobin, increase creatinine,  
increase urea, Increase AST, increase ALT,  
April 2024  
Initials…MU…….  
Page 15 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
increase alkaline phosphatase, increase bilirubin,  
hypokalaemia.  
c. Description of selected adverse reactions  
There have been isolated reports of necrosis after accidental extra-vascular administration and tumour  
lysis syndrome and anaphylaxis. The risk of myelodysplastic syndrome and acute myeloid leukemias  
is increased in patients treated with alkylating agents (including bendamustine). The secondary  
malignancy may develop several years after chemotherapy has been discontinued.  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows  
continued monitoring of the risk/benefit ratio of the medicine. Healthcare providers are asked to report  
any suspected adverse reactions to SAHPRA via ‘6.04 Adverse Drug Reactions Form’ available online  
under SAHPRA’s publications at https://www.sahpra.org.za/publications/Index/8/ or to the Holder of  
Certificate of Registration through the mail, pvg.cdma@heterodrugs.com. By reporting adverse  
reactions you can help provide more information on the safety of BENDAHET.  
4.9 Overdose  
After application of a 30 min infusion of bendamustine hydrochloride once every 3 weeks the  
maximum tolerated dose (MTD) was 280 mg/m2. Cardiac events of CTC (common toxicity scale)  
grade 2 which were compatible with ischaemic ECG changes occurred which were regarded as  
dose limiting.  
April 2024  
Initials…MU…….  
Page 16 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
In a subsequent study with a 30 min infusion of bendamustine hydrochloride at day 1 and 2 every 3  
weeks the MTD was found to be 180 mg/m2. The dose limiting toxicity was grade 4,  
thrombocytopenia. Cardiac toxicity was not dose limiting with this schedule.  
Counter measures:  
There is no specific antidote. Bone marrow transplantation and transfusions (platelets, concentrated  
erythrocytes) may be made, or haematological growth factors may be given as effective  
countermeasures to control haematological side effects. Bendamustine hydrochloride and its  
metabolites are dialysable to a small extent.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, ATC code: L01AA09  
Bendamustine hydrochloride is an alkylating antitumour agent. The antineoplastic and cytocidal effect  
of bendamustine hydrochloride is based essentially on a cross linking of DNA single and double strands  
by alkylation. As a result, DNA matrix functions and DNA synthesis and repair are impaired. The  
antitumour effect of bendamustine hydrochloride has been demonstrated by several in vitro studies in  
different human tumour cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian  
carcinoma and various leukaemias) and in-vivo in different experimental tumour models with tumours  
of mouse, rat and human origin (melanoma, breast cancer, sarcoma, lymphoma, leukaemia and small  
cell lung cancer). Bendamustine hydrochloride showed an activity profile in human tumour cell lines  
different to that of other alkylating agents. The active substance revealed no or very low cross-  
resistance in human tumour cell lines with different resistance mechanisms at least in part due to a  
comparatively persistent DNA interaction. Additionally, it was shown in clinical studies that there is no  
April 2024  
Initials…MU…….  
Page 17 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
complete cross-resistance of bendamustine with anthracyclines, alkylating agents or rituximab.  
However, the number of assessed patients is small.  
5.2 Pharmacokinetic properties  
Distribution  
The elimination half-life t1/2β after 30 min intravenous infusion of 120 mg/m2 area to 12 subjects was  
28,2 minutes. Following 30 min intravenous infusion the central volume of distribution was 19,3 L. Under  
steady-state conditions following intravenous bolus injection the volume of distribution was 15,8 – 20,5  
L.  
More than 95 % of the substance is bound to plasma proteins (primarily albumin).  
Biotransformation  
A
major route of clearance of bendamustine is the hydrolysis to monohydroxy- and  
dihydroxybendamustine. Formation of N-desmethyl-bendamustine and gamma-hydroxy-bendamustine  
by hepatic metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme.  
Another major route of bendamustine metabolism involves conjugation with glutathione.  
In-vitro bendamustine does not inhibit CYP 1A4, CYP 2C9/10, CYP 2D6, CYP 2E1 and CYP 3A4.  
Elimination  
The mean total clearance after 30 min intravenous infusion of 120 mg/m2 body surface area to 12  
subjects was 639,4 mL/minute. About 20 % of the administered dose was recovered in urine within 24  
hours. Amounts excreted in urine were in the order monohydroxy-bendamustine > bendamustine >  
April 2024  
Initials…MU…….  
Page 18 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
dihydroxy-bendamustine > oxidised metabolite> N-desmethyl bendamustine. In the bile, primarily polar  
metabolites are eliminated.  
Hepatic impairment  
In patients with 30 to 70 % tumour infestation of the liver and mild or moderate hepatic impairment  
[serum bilirubin < 2,0 mg/dl (34,2 μmol/L)] the pharmacokinetic behaviour was not changed.  
There was no significant difference to patients with normal liver and kidney function with respect to Cmax  
,
tmax, AUC, t1/2β, volume of distribution and clearance. AUC and total body clearance of bendamustine  
correlate inversely with serum bilirubin.  
Renal impairment  
In patients with creatinine clearance > 10 mL/min including dialysis dependent patients, no significant  
difference to patients with normal liver and kidney function was observed with respect to Cmax, tmax  
,
AUC, t1/2β, volume of distribution and clearance.  
Elderly subjects  
Subjects up to 84 years of age were included in pharmacokinetic studies. Higher age does not influence  
the pharmacokinetics of bendamustine.  
5.3 Preclinical safety data  
Not applicable  
April 2024  
Initials…MU…….  
Page 19 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
Mannitol  
6.2 Incompatibilities  
BENDAHET must not be mixed with other medicinal products except those mentioned in section 4.2  
6.3 Shelf life  
36 months  
Reconstituted concentrate:  
The powder should be reconstituted immediately after opening of the vial.  
The reconstituted concentrate should be diluted immediately with 0,9 % sodium chloride solution for  
injection.  
Solution for infusion: {3 hours and 1 day indicated in dossier}  
After reconstitution and dilution, chemical and physical stability has been demonstrated for 3,5 hours at  
25 °C and 2 days at 2 °C to 8 °C in polyethylene bags.  
From a microbiological point of view, the solution should be used immediately. If not used immediately,  
in-use storage times and conditions prior to use are the responsibility of the user.  
April 2024  
Initials…MU…….  
Page 20 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
6.4 Special precautions for storage  
Store at or below 25 °C.  
Keep the vial in the outer carton in order to protect from light.  
For storage conditions after reconstitution or dilution see section 6.3  
6.5 Nature and contents of container  
BENDAHET 25: 10 mL amber tubular Type 1 glass vial, with a grey rubber stopper and a blue flip off  
seal.  
BENDAHET 100: 20 mL amber tubular Type 1 glass vial, with a grey rubber stopper and a blue flip off  
seal.  
6.6 Special precautions for disposal and other handling  
The powder for concentrate for solution for infusion has to be reconstituted with water for injection,  
diluted with sodium chloride 9 mg/mL (0,9 %) solution for injection and then administered by intravenous  
infusion. Aseptic technique is to be used.  
1. Reconstitution  
−
−
Reconstitute each vial of BENDAHET containing 25 mg bendamustine hydrochloride in 5 mL  
water for injection by shaking.  
Reconstitute each vial of BENDAHET containing 100 mg bendamustine hydrochloride in 20  
mL water for injection by shaking.  
The reconstituted concentrate contains 5 mg bendamustine hydrochloride per mL and appears as a  
clear colourless solution.  
April 2024  
Initials…MU…….  
Page 21 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
2. Dilution  
As soon as a clear solution is obtained (usually after 5 – 10 minutes) dilute the total recommended dose  
of BENDAHET immediately with 0,9 % NaCl solution to produce a final volume of 500 mL.  
BENDAHET must be diluted with 0,9 % NaCl solution and not with any other injectable solution.  
3. Administration  
The solution is administered by intravenous infusion over 30 - 60 min.  
The vials are for single use only.  
Any unused product or waste material should be disposed of in accordance with local requirements.  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty). Ltd  
Waterfall Corporate Campus,  
Building No.2, First Floor,  
74 Waterfall Drive,  
Midrand, 2066  
Telephone number: 012 644 1220  
e-mail address: nokuthula.n@heterodrugs.com  
8 REGISTRATION NUMBER(S)  
April 2024  
Initials…MU…….  
Page 22 of 23  
Applicant/PHRC: Hetero Drugs South Africa (Pty). Ltd  
Product proprietary name: BENDAHET 25 & 100  
Dosage form and strength: Powder for concentrate for solution for infusion  
Each 10 mL vial contains 25 mg bendamustine hydrochloride  
Each 20 mL vial contains100 mg bendamustine hydrochloride  
BENDAHET 25: 51/26/2003  
BENDAHET 100: 51/26/2004  
9 DATE OF FIRST AUTHORISATION  
20 July 2021  
10 DATE OF REVISION OF THE TEXT  
24 April 2024  
April 2024  
Initials…MU…….  
Page 23 of 23