Summary of medicine characteristics - BENDAMUSTINE HYDROCHLORIDE AQVIDA 100 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION
1. NAME OF THE MEDICINAL PRODUCT
1. NAME OF THE MEDICINAL PRODUCTBendamustine Hydrochloride AqVida 100 mg/ ml concentrate for solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains bendamustine hydrochloride monohydrate corresponding to 50 mg bendamustine hydrochloride.
One vial contains bendamustine hydrochloride monohydrate corresponding to 100 mg bendamustine hydrochloride.
One vial contains bendamustine hydrochloride monohydrate corresponding to 200 mg bendamustine hydrochloride.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear colorless to yellow solution. The solution pH is in the range of 2.5 – 4.5 and the osmolality is between 230 an 330 mOsmol/kg.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
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 bendamustine hydrochloride on days 1 and 2; every 4 weeks up to 6 times.
Monotherapy for indolent non-Hodgkin’s lymphomas refractory to rituximab:
120 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2; every 3 weeks for at least 6 times.
Multiple myeloma:
120 – 150 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2, 60 mg/m2 body surface area prednisone i.v. or per os on days 1 to 4; every 4 weeks for at least 3 times.
Hepatic impairment:
On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment (serum bilirubin < 1.2mg/dl). A 30% dose reduction is recommended in patients with moderate hepatic impairment (serum bilirubin 1.2 – 3.0 mg/dl).
No data is available in patients with severe hepatic impairment (serum bilirubin values of > 3.0 mg/dl) (see section 4.3).
Renal impairment:
On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with a creatinine clearance of > 1 ml/min. Experience in patients with severe renal impairment is limited.
Paediatric population:
The safety and efficacy of bendamustine hydrochloride in children have not yet been established. Current available data is not sufficient to make a recommendation on posology.
Elderly:
There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).
Method of administration
For intravenous infusion over 30 – 60 minutes (see section 6.6).
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 shoul not be started if leukocyte and/or platelet values dropped to < 3,000/jrl or
< 75,000/jrl, respectively (see section 4.3).
Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to < 3,000/gl or < 75,000/gl, respectively. Treatment can be continued after leukocyte values have increased to > 4,000/gl and platelet values to : 100,000/gl.
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 CTCAE grades in the preceding cycle. A 50% dose reduction is recommended in case grade 3 toxicity. An interruption of treatment is recommended in case of grade 4 toxicity.
If a patient requires a dose modification the individually calculated reduced dose must be given on day 1 and 2 of th respective treatment cycle.
For instructions on dilution and administration of the medicinal product, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
During Breast-feeding
Severe hepatic impairment (serum bilirubin > 3.0 mg/dl)
Jaundice
Severe bone marrow suppression and severe blood count alterations (leukocyte and/or platelet values dropped to < 3,000/gl or < 75,000/gl, respectively)
Major surgery less than 30 days before start of treatment Infections, especially involving leukocytopenia
Yellow fever vaccination
4.4 Special warnings and precautions for use
Myelosuppression
Patients treated with bendamustine hydrochloride may experience myelosuppression. In the event of 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 > 4,000/gl or > 100,000/gl, respectively.
Infections
Serious and fatal infections have occurred with bendamustine hydrochloride, including bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus VZV) and cytomegalovirus (CMV). Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of bendamustine mainly in combination with rituximab or obinutuzumab. Treatment with bendmustine hydrochloride may cause prolonged lymphocytopenia (<600/^l) and low CD4-positive T-cell (T- helper cell) counts (<200/^l) for at least 7–9 months after the completion of treatment.
Lymphocytopenia and CD4-positive T-cell depletion are more pronounced when bendamustine is combined with rituximab Patients with lymphopenia and low CD4-positive T-cell count following treatment with bendamustine hydrochloride are more susceptible to (opportunistic) infections. In case of low CD4-positive T-cell counts (< 200/jil) Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered. All, patients should be monitored for respiratory signs and symptoms throughout treatment. Patients should be advised to report new signs of infection, including fever or respiratory symptoms promptly. Discontinuation of bendamustine hydrochloride should be considered if there are signs of (opportunistic) infections.
Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded.
Non-melanoma skin cancer
In clinical studies, an increased risk for non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) has been observed in patients treated with bendamustine containing therapies. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Hepatitis B reactivation
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received bendamustine hydrochloride. Some cases resulted in acute hepatic failure or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with bendamustine hydrochloride. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B tests (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with bendamustine hydrochloride should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).
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) and Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), some fatal, have been reported with the use of bendamustine hydrochloride. 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 events occurred when bendamustine hydrochloride was given in combination with other anticancer agents, so the precise relationship is uncertain. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, Bendamustine hydrochloride should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine hydrochloride is suspected, treatment should be discontinued.
Cardiac disorders
During treatment with bendamustine hydrochloride the concentration of potassium in the blood must be closely monitored and potassium supplement must be given If potassium levels <3,5 mEq/l, and ECG measurement must be performed.
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 may be given for the symptomatic treatment of nausea and vomiting.
Tumour lysis syndrome
Tumour lysis syndrome (TLS) associated with Bendamustine treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of Bendamustine and, without intervention, may lead to acute renal failure and death.
Preventive measures such as adequate hydration, close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of hypouricemic agents (allopurinol and rasburicase) should be considered prior to therapy.
There have been a few cases of Stevens – Johnson syndrome and Toxic Epidermal Necrolysis reported when bendamustine and allopurinol are administered concomitantly.
Anaphylaxis
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms are generally mild and include fever, chills, pruritus and rash. In rare instances 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.
Patients who experienced Grade 3 or worse allergic-type reactions were typically not re-challenged.
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 bendamustine hydrochloride 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.
4.5 Interaction with other medicinal products and other forms of interaction
No in-vivo interaction studies have been performed.
When Bendamustine hydrochloride is combined with myelosuppressive agents, the effect of Bendamustine hydrochloride and/or the co-administered medicinal products on the bone marrow may be potentiated. Any treatme reducing the patient’s performance status or impairing bone marrow function can increase the toxicity of Bendamustine hydrochloride.
Combination of Bendamustine hydrochloride with cyclosporine 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 metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see section 5.2). Therefore, potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir or cimetidine exists.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, Pregnancy and lactation
Pregnancy
There are insufficient data from the use of Bendamustine hydrochloride in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/fetolethal, teratogenic and genotoxic (see section 5.3). During pregnancy Bendamustine hydrochloride should not be used unless clearly necessary. The mother should be informed about the risk to the foetus. If treatment with Bendamustine hydrochloride is absolutely necessary during pregnancy or if pregnancy occurs during treatment, the patient should be informed about the risks for the unborn child and be monitored carefully. The possibility of genetic counseling should be considered.
Fertility
Women of childbearing potential must use effective methods of contraception both before and during Bendamustin hydrochloride therapy.
Men being treated with Bendamustine hydrochloride 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 Bendamustine hydrochloride.
Breast-feeding
It is not known whether bendamustine passes into the breast milk, therefore, Bendamustine hydrochloride is contraindicated during breast-feeding (see section 4.3). Breast-feeding must be discontinued during treatment with Bendamustine hydrochloride.
4.7 Effects on ability to drive and use machines
Bendamustine has major influence on the ability to drive and use machines. Ataxia, peripheral neuropathy and somnolence have been reported during treatment with Bendamustine hydrochloride (see section 4.8). Patients shoul be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.
4.8 Undesirable effects
The most common adverse reactions with bendamustine hydrochloride are hematological adverse reactions (leukopenia, thrombopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).
The table below reflects the data obtained with bendamustine hydrochloride.
| edDRA tem organ class | Very comm on > 1/10 | Common > 1/100 to <1/10 | Uncommon 1 1/1,000 to <1/100 | Rare > 1/10,000 to <1/1, 000 | Very rare <1/10, 000 | Not known (cannot be estimated from the available data) |
| tions and ations | Infection NOS* Including Opportunistic infection (including Herpes zoster, cytomegalovir us, hepatitis B) | Pneumocystis jirovecii pneumonia | Sepsis | Pneumonia primary atypical | ||
| lasma n, nant and cified ding cyst olyp) | Tumour lysis syndrome | Myelodyspla s tic syndrome, acute myeloid leukemia | ||||
| d and hatic system ders | Leukopenia NOS*, Thrombocytope nia, Lymphopenia | Haemorrhage, Anaemia, Neutropenia | Pancytopenia | Bone marrow failure | Haemolysis | |
| ne system ders | Hypersensitivi t y NOS* | Anaphylactic reaction, Anaphylactoid reaction | Anaphylactic shock | |||
| ous system ders | Headache | Insomnia Dizziness | Somnolence, Aphonia | Dysgeusia, Paraesthesia, Peripheral sensory neuropathy, Anticholinergi c syndrome, Neurological disorders, Ataxia, Encephalitis | ||
| ac ders | Cardiac dysfunction, such as palpitations, angina pectoris, Arrhythmia | Pericardial effusion, Myocardial infarction, Cardiac failure | Tachycardia | Atrial fibrillatio n | ||
| ular ders | Hypotensio n, Hypertensio | Acute circulator y failure | Phlebitis |
| n | ||||||
| ratory, cic and -stinal ders | Pulmonar y dysfunctio n | Pulmonar y fibrosis | Pneumonitis, pulmonary alveolar haemorrhage | |||
| ointestinal ders | Nausea, Vomiting | Diarrhoea, Constipation, Stomatitis | haemorrhagic oesophagitis, Gastrointestinal haemorrhage | |||
| and taneous disorders | Alopecia, Skin disorders NOS*, | Erythema, Dermatitis, Pruritus, | Stevens-Johnson syndrome, |
| )RA em class | Very common 1 1/10 | Common > 1/100 to <1/10 | Uncommon 1 1/1,000 to <1/100 | Rare > 1/10,000 to <1/1, 000 | Very rare <1/10, 000 | Not known (cannot be estimated from the available data) |
| Urticaria | maculopapular rash, Hyperhidrosis | Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)* | ||||
| ctive nd sorders | Amenorrhea | Infertility | ||||
| iliary | Hepatic failure | |||||
| ratio ns | Mucosal inflammation, Fatigue, Pyrexia | Pain, Chills, Dehydration, Anorexia | Multi organ failure | |||
| itions | Haemoglobi n decrease, Creatinine increase, Urea increase | AST increase, ALT increase, Alkaline phosphatase increase, Bilirubin increase, Hypokalemia | ||||
| d lisorders | Renal failure |
NOS = Not otherwise specified (*=combination therapy with rituximab)
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 leukaemias is increased in patients treated with alkylating agents (including bendamustine). The secondary malignancy may develop several years after chemotherapy has bee discontinued.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard), or search for
MHRA Yellow Card in the Google Play or Apple App Store.
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 CTCAE grade 2 which were compatible with ischaemic ECG changes occurred which were regarded as dose- limiting. 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 haematologica side-effects.
Bendamustine hydrochloride and its metabolites are dialyzable 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 with unique activity. The antineoplastic and cytocida 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, ovary carcinoma and different leukaemia) 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 complete cross-resistance of bendamustine with anthracyclines, alkylating agents or rituximab. However, the number of assessed patients is small.
Chronic lymphocytic leukaemia
The indication for use in chronic lymphocytic leukaemia is supported by a single open label study comparing bendamustine with chlorambucil. In a the prospective, multi-centre, randomised, study, 319 previously untreated patients with chronic lymphocytic leukaemia stage Binet B or C requiring therapy were included. The first line therapy with bendamustine hydrochloride 100 mg/m2 i.v. on days 1 and 2 (BEN) was compared to treatment with chlorambucil 0.8mg/kg days 1 and 15 (CLB) for 6 cycles in both arms. Patients received allopurinol in order to prevent tumour lysis syndrome.
Patients with BEN have a significantly longer median progression free survival than patients with CLB treatment (21.5 versus 8.3 months, p < 0.0001 in the latest follow-up). Overall survival was not statistically significantly different (median not reached). The median duration of remission is 19 months with BEN and 6 months with CLB treatment (p < 0.0001). The safety evaluation in both treatment arms did not reveal any unexpected undesirable effects in nature and frequency. The dose of BEN was reduced in 34% of the patients. Treatment with BEN was discontinued in 3.9% of patients due to allergic reactions.
Indolent non-Hodgkin’s lymphomas
The indication for indolent non-Hodgkin’s lymphomas relied on two uncontrolled phase II trials.
In the pivotal prospective, multi-centre, open study 100 patients with indolent B-cell non-Hodgkin's lymphomas refractory to rituximab mono- or combination therapy were treated with BEN single agent. Patients received a median of 3 previous chemotherapy or biologic therapy courses. The median number of previous rituximabcontaining courses was 2. The patients had no response or progress within 6 months after rituximab treatment. The dose of BEN was 120 mg/m2 i.v. on days 1 and 2 planned for at least 6 cycles. Duration of treatment depended on response (6 cycles planned). The overall response rate was 75% including 17% complete (CR and CRu) and 58% partial response as assessed by independent review committee. The median duration of remission was 40 weeks. BEN was generally well tolerated when given in this dose and schedule.
The indication is further supported by another prospective, multi-centre, open study including 77 patients. The patient population was more heterogeneous including: indolent or transformed B-cell non-Hodgkin’s lymphomas refractory to rituximab mono- or combination therapy. The patients had no response or progress within 6 months or had an untoward reaction to prior rituximab treatment. Patients received a median of 3 previous chemotherapy or biological therapy courses. The median number of previous rituximab-containing courses was 2. The overall response rate was 76% with a median duration of response of 5 months (29 [95% CI 22.1, 43.1] weeks).
Multiple myeloma
In a prospective, multi-centre, randomised, open study 131 patients with advanced multiple myeloma (Durie-Salmo stage II with progress or stage III) were included. The first line therapy with bendamustine hydrochloride in combination with prednisone (BP) was compared to treatment with melphalan and prednisone (MP). Tolerability in both treatment arms was in line with the known safety profile of the respective medicinal products with significantl more dose reductions in the BP arm.. The dose was bendamustine hydrochloride 150 mg/m2 i.v. on days 1 and 2 or melphalan 15 mg/m2 i.v. on day 1 each in combination with prednisone. Duration of treatment depended on respons and averaged 6.8 in the BP and 8.7 cycles in the MP group.
Patients with BP treatment have a longer median progression free survival than patients with MP (15 [95%Cl 12–21 versus 12 [95%Cl 10–14] months) (p=0.0566). The median time to treatment failure is 14 months with BP and 9 months with MP treatment. The duration of remission is 18 months with BP and 12 months with MP treatment. The difference in overall survival is not significantly different (35 months BP versus 33 months MP). Tolerability in bot treatment arms was in line with the know safety profile of the respective medicinal products with significantly more dose reductions in the BP arm.
5.2 Pharmacokinetic properties
Distribution
The elimination half-life t1/2B after 30 min i.v. infusion of 120 mg/m2 area to 12 subjects was 28.2 minutes.
Following 30 min i.v. infusion the central volume of distribution was 19.3 l. Under steady-state conditions followin i.v. 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 dihydroxy- bendamustine. 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 i.v. 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 > dihydroxy-bendamustine > oxidised metabolite > N-desmethyl bendamustine. In the bile, primarily polar metabolites are eliminated.
Hepatic impairment
In patients with 30 – 70% tumour infestation of the liver and mild hepatic impairment (serum bilirubin
< 1.2 mg/dl) 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, t1/2B , 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, t1/2B, 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
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposur levels and with possible relevance to clinical use were as follows:
Histological investigations in dogs showed macroscopic visible hyperaemia of the mucosa and haemorrhagia in the gastrointestinal tract. Microscopic investigations showed extensive changes of the lymphatic tissue indicating an immunosuppression and tubular changes of kidneys and testis, as well as atrophic, necrotic changes of the prostate epithelium.
Animal studies showed that bendamustine is embryotoxic and teratogenic.
Bendamustine induces aberrations of the chromosomes and is mutagenic in-vivo as well as in-vitro. In long-term studies in female mice bendamustine is carcinogenic.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
N,N-Dimethylacetamide
Sucrose
L-Cysteine hydrochloride monohydrate (E920)
Water for injection
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Before dilution:
2 years
After dilution:
Physicochemical stability of the diluted solution has been demonstrated for 3.5 hours at 25 °C/ 60%RH and 2 days i 2°C to 8°C in polyvinylchloride 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 and would normally not be longer than 24 hours at 2 to 8°C unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Type I amber glass vials of 2 ml with chlorobutyl rubber stopper and an aluminium flip-off seal.
Pack size:
Vials containing 0.5ml (50mg), 1.0ml (100mg) and 2.0ml (200mg) Bendamustine Hydrochloride AqVida, supplied in packs of 1 and 5 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalThe concentration of Bendamustine Hydrochloride AqVida differs from other Bendamustine containing products. It must be diluted before use.
Handling:
The normal safety precautions for cytostatic agents must be observed when preparing and disposing of the infusion solution. Handling of the solution for infusion should be done in a safety box and protective coats and gloves shoul be used. If no safety box is available, the equipment should be supplemented with a mask and protective glasses.
When handling Bendamustine Hydrochloride AqVida, 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 o special safety workbenches (laminar flow) with liquid impermeable, absorbing disposable foil. Pregnant personnel should be excluded from handling cytostatics. If there is lasting irritation, a doctor should be consulted. If the solution is spilled on the skin, rinse thoroughly with water.
Instructions for dilution:
The only approved diluent for dilution of Bendamustine Hydrochloride AqVida is sodium chloride 9 mg/ml (0.9%) solution for injection (without preservative). The diluted bag is fabricated from a polyvinylchloride (PL 146 Plastic 1. Use aseptic techniques preparation for Bendamustine Hydrochloride AqVida administration.
2. The total quantity of the Bendamustine Hydrochloride AqVida required for an individual patient should be diluted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative to produce a final volume of about 500 ml, yielding a concentration between 0.3 mg/ml and 0.6 mg/ml. The diluted solution is a clear colourless to yellow solution.
Preparation of the infusion solution:
If the vials are stored under refrigeration, allow the required number of boxes of Bendamustine Hydrochloride AqVida to stand below 25°C for 5 minutes before use. More than one vial of Bendamustine Hydrochloride AqVida may be necessary to obtain the required dose for the patient (see Table 1).
Aseptically withdraw the required amount of Bendamustine hydrochloride using a calibrated syringe.
The required volume of Bendamustine Hydrochloride AqVida must be injected into an infusion bag containing 0.9 sodium chloride solution for infusion to produce final volume of 500 ml. Do not add other medicinal products to th prepared infusion solution or intravenous infusion set.
Mix the infusion bag manually using a rocking motion. Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of in accordance with local requirements.
As with all parenteral medicinal products, Bendamustine Hydrochloride AqVida solution should be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.
The details are given in below table 1 for the total dose and volume required for the typical body surface area and no. of vials required.
Table 1: Sample calculations for patients receiving the recommended dose of 100 mg/m2 – 150 mg/m2 of bendamustine for body surface area ranging from 1.6 m2 to 2 m2
For chronic lymphocytic leukaemia:
| ypical Body urface Area (M2) | Total dose = patient BSA multiplied by recommended dose | Total volume to be diluted to 500 ml [100 mg/ml]) | Number of vials needed |
| Monotherapy for chronic lymphocytic leukaemia: 100 mg/m2 | |||
| mg | ml | ||
| 1.6 | 160 | 1.6 | 1 vial of 200 mg |
| 1.7 | 170 | 1.7 | 1 vial of 200 mg |
| 1.8 | 180 | 1.8 | 1 vial of 200 mg |
| 1.9 | 190 | 1.9 | 1 vial of 200 mg |
| 2 | 200 | 2 | 1 vial of 200 mg |
For indolent non-Hodgkin’s lymphomas refractory to rituximab:
| pical Body rface Area (M2) | Total dose = patient BSA multiplied by recommended dose | Total volume to be diluted to 500 ml [100 mg/ml]) | ber of vials needed |
| Monotherapy for indolent non-Hodgkin’s lymphomas refractory to rituximab: | |||
| 120mg/m2 | |||
| mg | ml | ||
| 1.6 | 192 | 1.9 | 1 vial of 200 mg |
| 1.7 | 204 | 2.0 | 1 vial of 200 mg |
| 1.8 | 216 | 2.2 | 1 vial of 200 mg + 1 vial of 50 mg |
| 1.9 | 228 | 2.3 | 1 vial of 200 mg + 1 vial of 50 mg |
| 2 | 240 | 2.4 | 1 vial of 200 mg + 1 vial of 50 mg |
For Multiple myeloma:
| ypical Body urface Area (M2) | Total dose = patient BSA multiplied by recommended dose | Total volume to be diluted to 500 ml [100 mg/ml]) | Number of vials needed |
| Multiple myeloma: 120–150 mg/ m2 | |||
| mg | ml | ||
| 1.6 | 192–240 | 1.9–2.4 | 1 vial of 200 mg – 1 vial of 200 mg + 1 vial of 50 mg |
| 1.7 | 204–255 | 2.0–2.5 | 1 vial of 200 mg – 1 vial of 200 mg + 1 vial of 50 mg |
| 1.8 | 216–270 | 2.2–2.7 | 1 vial of 200 mg + 1 vial of 50 mg – 1 vial of 200 mg + 1 vial of 100 mg |
| 1.9 | 228–285 | 2.3–2.9 | 1 vial of 200 mg + 1 vial of 50 mg – 1 vial of 200 mg + 1 vial of 100 mg |
| 2 | 240–300 | 2.4–3.0 | 1 vial of 200 mg + 1 vial of 50 mg – 1 vial of 200 mg + 1 vial of 100 mg |
Administration:
The required solution is administered by slow intravenous infusion over 30–60 min period.
The vials are for single use only.
Since no antimicrobial preservative is included, dilution must be carried out under full aseptic conditions. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Unintentional injection into the tissue outside blood vessels (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 (see section 4.4
7 MARKETING AUTHORISATION HOLDER
AqVida GmbH,
Kaiser-Wilhelm Strasse 89,
20355 Hamburg, Germany
8 MARKETING AUTHORISATION NUMBER(S)
PL 40397/0004
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/03/2019