Drugs List

Therapeutic Indications

Uses

B-cell chronic lymphocytic leukaemia where fludarabine inappropriate
Combination treatment of multiple myeloma in patients over 65
Non-Hodgkin's lymphomas - secondary therapy

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.

Administration

For intravenous infusion over 30 to 60 minutes.

Contraindications

Children under 18 years
Infection
Leucocyte count below 3 x 10 to the power of 9 / L
Platelet count below 75 x 10 to the power of 9 / L
Within 30 days of major surgery
Breastfeeding
Jaundice
Pregnancy
Severe hepatic impairment
Severe myelosuppression

Precautions and Warnings

Leucocyte count below 4 x 10 to the power of 9 / L
Platelet count below 100 x 10 to the power of 9/ L
Risk factors for skin cancer
Dehydration
History of cardiac disorder
History of hepatitis B
Moderate hepatic impairment - serum bilirubin between 1.2mg and 3mg/dl
Myelosuppression
Severe renal impairment

Advise ability to drive/operate machinery may be affected by side effects
Anti-emetics may be required during therapy
Before initiating screen all patients for hepatitis B infection
CD4+ T-cell count below 200 per microlitre: Consider PJP prophylaxis
Consider premedication for patients with history of infusion reactions
Consider premedication with hypouricaemic agent
Give pre-treatment counselling and consideration of sperm cryopreservation
Hepatitis B: Refer prior to initiation to liver disease specialist
Maintain adequate hydration of patient prior / during treatment
Monitor patients for non-melanoma skin cancer prior to and during treatment
Consult local policy on the safe use of anti-cancer drugs
If extravasation occurs follow local policy & seek expert help immediately
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Consider PTLD or PML if new or worsening neurological symptoms occur
If rash develops, consider possibility of Stevens-Johnson Syndrome
Increase monitoring of ECG when serum potassium below 3.5mEq/l
Monitor ECG prior to and during treatment in existing cardiac abnormalities
Monitor for active hepatitis B during therapy and for several months after
Monitor full blood counts weekly
Monitor patient for infusion-associated reactions (IARs)
Monitor patients for signs of tumour lysis syndrome
Monitor respiratory function
Monitor serum potassium in patients with cardiac disorders
Monitor uric acid levels
Advise patient to report headaches, seizures, confusion, visual disturbance
Advise patient to report symptoms of infection immediately
May affect immune response to live vaccines
Potassium supplements may be required
Potentially mutagenic and carcinogenic
Reactivation of hepatitis B may occur in chronic carriers
Secondary tumours may occur as long-term sequelae
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Discontinue if serious allergic or anaphylactic reaction occurs
Discontinue if severe skin reaction occurs
Discontinue treatment if progressive skin rash occurs
Suspend treatment if opportunistic infection is suspected
Interrupt treatment if grade 4 non-haematological toxicity occurs
Reduce dose if grade 3 non-haematological toxicity occurs
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 6 months after treatment
Advise patient to inform physician of any skin changes immediately

Patients with lymphocytopenia and low CD-4 positive T-cell counts have an increased susceptibility to opportunistic infections during and up to 9 months after discontinuing treatment, particularly in patients treated with concomitant rituximab.

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) has been reported in some patients treated with this agent, usually in combination with rituximab or obinutuzumab. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed. If PML is diagnosed, treatment should be permanently discontinued.

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 greater than 4000 per microlitre or greater than 100,000 per microlitre respectively.

Pregnancy and Lactation

Pregnancy

Bendamustine is contraindicated during pregnancy.

The manufacturer recommends that bendamustine should not be used during pregnancy unless clearly necessary. In non-clinical studies bendamustine was shown to be mutagenic and teratogenic. If the use of bendamustine is absolutely necessary during pregnancy or inadvertent pregnancy occurs during treatment, the woman should be advised of the possible risk for severe adverse effects in the embryo and fetus.

Lactation

Bendamustine is contraindicated during breastfeeding.

Use of bendamustine when breastfeeding is contraindicated by the manufacturer. The manufacturer recommends that breastfeeding must be discontinued during bendamustine treatment. It is not known whether this agent or its metabolites are excreted in human breast milk. Effects on exposed infants are unknown.

The effect of concurrent therapies must also be considered.

Side Effects

Acute myeloid leukaemia
Alopecia
Amenorrhoea
Anaemia
Anaphylactic reaction
Anaphylactic shock
Anaphylactoid reaction
Angina pectoris
Anorexia
Anticholinergic effects
Aphonia
Arrhythmias
Ataxia
Atrial fibrillation
Blood urea increased
Bone marrow failure
Cardiac disorders
Cardiac failure
Chills
Circulatory failure
Constipation
Cytomegalovirus infection
Dehydration
Dermatitis
Diarrhoea
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysgeusia
Dysphonia
Encephalitis
Erythema
Extravasation
Fatigue
Gastro-intestinal haemorrhage
Haemoglobin decrease
Haemolysis
Haemorrhage
Headache
Hepatic failure
Hyperhidrosis
Hypersensitivity reactions
Hypertension
Hypokalaemia
Hypotension
Increase in alkaline phosphatase
Increase in creatinine
Increase in serum ALT/AST
Infections
Infertility
Insomnia
Leukopenia
Lymphopenia
Maculopapular rash
Mucosal inflammation
Multiorgan failure
Myelodysplastic syndrome
Myocardial infarction
Nausea
Neoplasms
Neurological disorders
Neutropenia
Oesophagitis
Opportunistic infections
Pain
Palpitations
Pancytopenia
Paraesthesia
Pericardial effusion
Peripheral neuropathy
Phlebitis
Pneumocystis jiroveci pneumonia
Pneumonia
Pneumonitis
Progressive multifocal leukoencephalopathy (PML)
Pruritus
Pulmonary disorder
Pulmonary fibrosis
Pyrexia
Reactivation of hepatitis B
Renal failure
Sepsis
Serum bilirubin increased
Skin disorder
Somnolence
Stevens-Johnson syndrome
Stomatitis
Tachycardia
Thrombocytopenia
Toxic epidermal necrolysis
Tumour lysis syndrome
Urticaria
Vomiting

Presentation

Infusions containing bendamustine hydrochloride.

Drugs List

Therapeutic Indications

Uses

B-cell chronic lymphocytic leukaemia where fludarabine inappropriate
Combination treatment of multiple myeloma in patients over 65
Non-Hodgkin's lymphomas - secondary therapy

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.

Dosage

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Doses may vary significantly if this agent is used as monotherapy or different combinations.
When using this agent, specialist literature, national guidelines, cancer network protocols and Trust chemotherapy protocols should be consulted.

Adults

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For intravenous infusion over 30 to 60 minutes.

Contraindications

Children under 18 years
Infection
Leucocyte count below 3 x 10 to the power of 9 / L
Platelet count below 75 x 10 to the power of 9 / L
Within 30 days of major surgery
Breastfeeding
Jaundice
Pregnancy
Severe hepatic impairment
Severe myelosuppression

Precautions and Warnings

Leucocyte count below 4 x 10 to the power of 9 / L
Platelet count below 100 x 10 to the power of 9/ L
Risk factors for skin cancer
Dehydration
History of cardiac disorder
History of hepatitis B
Moderate hepatic impairment - serum bilirubin between 1.2mg and 3mg/dl
Myelosuppression
Severe renal impairment

Advise ability to drive/operate machinery may be affected by side effects
Anti-emetics may be required during therapy
Before initiating screen all patients for hepatitis B infection
CD4+ T-cell count below 200 per microlitre: Consider PJP prophylaxis
Consider premedication for patients with history of infusion reactions
Consider premedication with hypouricaemic agent
Give pre-treatment counselling and consideration of sperm cryopreservation
Hepatitis B: Refer prior to initiation to liver disease specialist
Maintain adequate hydration of patient prior / during treatment
Monitor patients for non-melanoma skin cancer prior to and during treatment
Consult local policy on the safe use of anti-cancer drugs
If extravasation occurs follow local policy & seek expert help immediately
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Consider PTLD or PML if new or worsening neurological symptoms occur
If rash develops, consider possibility of Stevens-Johnson Syndrome
Increase monitoring of ECG when serum potassium below 3.5mEq/l
Monitor ECG prior to and during treatment in existing cardiac abnormalities
Monitor for active hepatitis B during therapy and for several months after
Monitor full blood counts weekly
Monitor patient for infusion-associated reactions (IARs)
Monitor patients for signs of tumour lysis syndrome
Monitor respiratory function
Monitor serum potassium in patients with cardiac disorders
Monitor uric acid levels
Advise patient to report headaches, seizures, confusion, visual disturbance
Advise patient to report symptoms of infection immediately
May affect immune response to live vaccines
Potassium supplements may be required
Potentially mutagenic and carcinogenic
Reactivation of hepatitis B may occur in chronic carriers
Secondary tumours may occur as long-term sequelae
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Discontinue if serious allergic or anaphylactic reaction occurs
Discontinue if severe skin reaction occurs
Discontinue treatment if progressive skin rash occurs
Suspend treatment if opportunistic infection is suspected
Interrupt treatment if grade 4 non-haematological toxicity occurs
Reduce dose if grade 3 non-haematological toxicity occurs
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 6 months after treatment
Advise patient to inform physician of any skin changes immediately

Patients with lymphocytopenia and low CD-4 positive T-cell counts have an increased susceptibility to opportunistic infections during and up to 9 months after discontinuing treatment, particularly in patients treated with concomitant rituximab.

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) has been reported in some patients treated with this agent, usually in combination with rituximab or obinutuzumab. If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed. If PML is diagnosed, treatment should be permanently discontinued.

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 greater than 4000 per microlitre or greater than 100,000 per microlitre respectively.

Pregnancy and Lactation

Pregnancy

Bendamustine is contraindicated during pregnancy.

The manufacturer recommends that bendamustine should not be used during pregnancy unless clearly necessary. In non-clinical studies bendamustine was shown to be mutagenic and teratogenic. If the use of bendamustine is absolutely necessary during pregnancy or inadvertent pregnancy occurs during treatment, the woman should be advised of the possible risk for severe adverse effects in the embryo and fetus.

Lactation

Bendamustine is contraindicated during breastfeeding.

Use of bendamustine when breastfeeding is contraindicated by the manufacturer. The manufacturer recommends that breastfeeding must be discontinued during bendamustine treatment. It is not known whether this agent or its metabolites are excreted in human breast milk. Effects on exposed infants are unknown.

The effect of concurrent therapies must also be considered.

Side Effects

Acute myeloid leukaemia
Alopecia
Amenorrhoea
Anaemia
Anaphylactic reaction
Anaphylactic shock
Anaphylactoid reaction
Angina pectoris
Anorexia
Anticholinergic effects
Aphonia
Arrhythmias
Ataxia
Atrial fibrillation
Blood urea increased
Bone marrow failure
Cardiac disorders
Cardiac failure
Chills
Circulatory failure
Constipation
Cytomegalovirus infection
Dehydration
Dermatitis
Diarrhoea
Dizziness
Drug rash with eosinophilia and systemic symptoms (DRESS)
Dysgeusia
Dysphonia
Encephalitis
Erythema
Extravasation
Fatigue
Gastro-intestinal haemorrhage
Haemoglobin decrease
Haemolysis
Haemorrhage
Headache
Hepatic failure
Hyperhidrosis
Hypersensitivity reactions
Hypertension
Hypokalaemia
Hypotension
Increase in alkaline phosphatase
Increase in creatinine
Increase in serum ALT/AST
Infections
Infertility
Insomnia
Leukopenia
Lymphopenia
Maculopapular rash
Mucosal inflammation
Multiorgan failure
Myelodysplastic syndrome
Myocardial infarction
Nausea
Neoplasms
Neurological disorders
Neutropenia
Oesophagitis
Opportunistic infections
Pain
Palpitations
Pancytopenia
Paraesthesia
Pericardial effusion
Peripheral neuropathy
Phlebitis
Pneumocystis jiroveci pneumonia
Pneumonia
Pneumonitis
Progressive multifocal leukoencephalopathy (PML)
Pruritus
Pulmonary disorder
Pulmonary fibrosis
Pyrexia
Reactivation of hepatitis B
Renal failure
Sepsis
Serum bilirubin increased
Skin disorder
Somnolence
Stevens-Johnson syndrome
Stomatitis
Tachycardia
Thrombocytopenia
Toxic epidermal necrolysis
Tumour lysis syndrome
Urticaria
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: February 2019

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Summary of Product Characteristics: Bendamustine hydrochloride 25mg/ml concentrate for solution for infusion. Accord UK Ltd. February 2022.
Summary of Product Characteristics: Levact 2.5mg/ml powder for concentrate for solution for infusion. Napp Pharmaceuticals Ltd. January 2019.
Summary of Product Characteristics: Bendamustine powder for concentrate for solution for infusion. Actavis UK Ltd. February 2018.
Summary of Product Characteristics: Bendamustine hydrochloride 2.5mg/ml powder for concentrate for solution for infusion. Accord UK Ltd. December 2020.
Summary of Product Characteristics: Bendamustine hydrochloride 2.5mg/ml powder for concentrate for solution for infusion. Dr Reddy's UK Ltd. February 2019.
Summary of Product Characteristics: Bendamustine hydrochloride 180mg/4mg/ml powder for concentrate for solution for infusion. Dr Reddy's UK Ltd. February 2019.

HPRA Safety Notice June 2017
https://www.hpra.ie/homepage/medicines/safety-notices
Last accessed: 25 August 2017.

MHRA Drug Safety Update July 2017
Available at: https://www.mhra.gov.uk
Last accessed: 25 August 2017.

MHRA Drug Safety Update March 2021 Available at: https://www.mhra.gov.uk
Last accessed: 16 March 2022.
NICE Evidence Services
Available at: www.nice.org.uk
Last accessed: 16 March 2022.