Bendamustine

Bendamustine hydrochloride is an alkylating antitumour agent. Its antineoplastic and cell-killing effects rest mainly on cross-linking of single and double DNA strands by alkylation, which disturbs the function of the DNA template and DNA synthesis and repair.

Mechanism of Action

• Alkylation: bendamustine is a bifunctional nitrogen mustard derivative that forms electrophilic alkyl groups binding covalently to other molecules. The resulting intra- and inter-strand cross-links lead to cell death. It acts on both dividing and resting cells, although the exact mechanism is not fully known.
• Activity profile: in human tumour cell lines its activity profile differs from that of other alkylating agents. There was little or no cross-resistance in cell lines with different resistance mechanisms, partly because of a comparatively persistent interaction with DNA. Clinical studies also show no complete cross-resistance with anthracyclines, alkylating agents or rituximab, although few patients were evaluated.
• Active metabolites: two minor active metabolites, M3 and M4, are formed through CYP1A2, but their plasma concentrations are about one tenth and one hundredth of the parent compound, so the cytotoxic activity is mainly due to bendamustine itself.

Pharmacokinetics

• Absorption: bendamustine is given by intravenous infusion, so absorption does not apply; peak concentration typically occurs at the end of the infusion.
• Distribution: after a 30-minute infusion of 120 mg/m², the elimination half-life (t½β) in 12 patients was 28.2 minutes and the central volume of distribution 19.3 L. The steady-state volume after an intravenous bolus was 15.8 to 20.5 L. More than 95% is bound to plasma proteins, mainly albumin.
• Metabolism: an important route is hydrolysis to monohydroxy- and dihydroxy-bendamustine, which have low cytotoxic activity. CYP1A2 forms N-desmethyl- and gamma-hydroxy-bendamustine in the liver, and conjugation with glutathione is another major route. In vitro, bendamustine does not inhibit CYP2C9/10, 2D6, 2E1 or 3A4.
• Elimination: mean total clearance was 639.4 mL/min in 12 patients after a 30-minute infusion of 120 mg/m². About 20% of the dose appeared in urine within 24 hours, mainly as monohydroxy-bendamustine, then bendamustine, dihydroxy-bendamustine, an oxidised metabolite and N-desmethyl-bendamustine. Polar metabolites are excreted mainly in bile.
• Special populations: in mild hepatic impairment (serum bilirubin below 1.2 mg/dL, with 30–70% tumour involvement of the liver) pharmacokinetics were unchanged, but AUC and total clearance correlated inversely with serum bilirubin. Patients with creatinine clearance above 10 mL/min, including dialysis patients, did not differ significantly from those with normal function. Age (studied up to 84 years) did not affect pharmacokinetics.

• Chronic lymphocytic leukaemia (CLL): first-line treatment of CLL (Binet stage B or C) in patients for whom combination chemotherapy with fludarabine is not appropriate.
• Indolent non-Hodgkin lymphoma: monotherapy in patients with indolent non-Hodgkin lymphomas who have progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
• Multiple myeloma: first-line treatment of multiple myeloma (Durie-Salmon stage II with progression, or stage III), in combination with prednisone, in patients older than 65 years who are not candidates for autologous stem cell transplantation and who have clinical neuropathy at diagnosis that precludes thalidomide- or bortezomib-based treatment.

• Hypersensitivity to the active substance or to any of the excipients.
• Breastfeeding.
• Severe hepatic impairment (serum bilirubin above 3.0 mg/dL).
• Jaundice.
• Severe bone marrow suppression and severe blood count changes (leucocytes below 3,000/μL or platelets below 75,000/μL).
• Major surgery within the 30 days before treatment starts.
• Infections, especially with leucocytopenia.
• Yellow fever vaccination.

The most frequent reactions are haematological (leukopenia, thrombocytopenia), dermatological (allergic reactions), constitutional (fever) and digestive (nausea, vomiting).

Very common (≥1/10): infections (unspecified, including opportunistic infections such as herpes zoster, cytomegalovirus and hepatitis B), leukopenia, thrombocytopenia, lymphopenia, headache, nausea, vomiting, mucosal inflammation, fatigue, pyrexia, decreased haemoglobin, increased creatinine and urea.

Common (≥1/100 to <1/10): tumour lysis syndrome, haemorrhage, anaemia, neutropenia, hypersensitivity, insomnia, dizziness, cardiac dysfunction (palpitations, angina pectoris, arrhythmia), hypotension, hypertension, pulmonary dysfunction, diarrhoea, constipation, stomatitis, alopecia, skin disorders, urticaria, amenorrhoea, pain, chills, dehydration, anorexia, increased ALT, AST, alkaline phosphatase and bilirubin, hypokalaemia.

Uncommon (≥1/1,000 to <1/100): Pneumocystis jirovecii pneumonia, myelodysplastic syndrome, acute myeloid leukaemia, pancytopenia, pericardial effusion, myocardial infarction, cardiac failure.

Rare (≥1/10,000 to <1/1,000): sepsis, bone marrow failure, anaphylactic and anaphylactoid reactions, somnolence, aphonia, acute circulatory failure, erythema, dermatitis, pruritus, maculopapular rash, hyperhidrosis.

Very rare (<1/10,000): primary atypical pneumonia, haemolysis, anaphylactic shock, dysgeusia, paraesthesia, peripheral sensory neuropathy, anticholinergic syndrome, neurological disorders, ataxia, encephalitis, tachycardia, phlebitis, pulmonary fibrosis, haemorrhagic oesophagitis, gastrointestinal haemorrhage, infertility, multiple organ failure.

Not known: atrial fibrillation, pneumonitis, pulmonary alveolar haemorrhage, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS, reported with rituximab), hepatic failure, renal failure, nephrogenic diabetes insipidus.

Isolated cases of necrosis after accidental extravascular administration have been reported, as have isolated cases of tumour lysis and anaphylaxis. The risk of myelodysplastic syndrome and acute myeloid leukaemia is higher in patients treated with alkylating agents, including bendamustine, and a secondary malignancy can develop several years after chemotherapy has stopped.

No in vivo interaction studies have been performed, and interaction studies were done in adults only.

• Myelosuppressive agents: they can potentiate the effect on bone marrow. Any treatment that lowers the patient’s performance status or impairs bone marrow function can increase toxicity.
• Ciclosporin or tacrolimus: the combination may cause excessive immunosuppression with a risk of lymphoproliferation.
• Live virus vaccines: cytostatic medicines can reduce antibody formation after vaccination with live viruses and raise the risk of infection, which can be fatal; the risk is greater in people already immunocompromised by their illness. Yellow fever vaccination is contraindicated.
• CYP1A2 inhibitors: because bendamustine is metabolised partly by CYP1A2, interactions are possible with inhibitors such as fluvoxamine, ciprofloxacin, aciclovir and cimetidine.
• Allopurinol: a few cases of Stevens-Johnson syndrome and toxic epidermal necrolysis were reported when bendamustine and allopurinol were given together.

Bendamustine is given as an intravenous infusion over 30 to 60 minutes, under the supervision of a qualified physician experienced in the use of chemotherapeutic agents. Poor bone marrow function increases chemotherapy-induced haematological toxicity. Treatment is not started if leucocytes are below 3,000/μL or platelets below 75,000/μL, and it is interrupted or delayed if they fall below these levels. It can resume when leucocytes are above 4,000/μL and platelets above 100,000/μL. Leucocyte and platelet counts reach their lowest point after 14 to 20 days and recover after 3 to 5 weeks, so blood counts are monitored strictly between cycles. Preparation and administration instructions are in section 6.6 of the SmPC.

Recommended Dose

• Chronic lymphocytic leukaemia (monotherapy): 100 mg/m² of body surface area on days 1 and 2, every 4 weeks, up to 6 times.
• Indolent non-Hodgkin lymphoma refractory to rituximab (monotherapy): 120 mg/m² on days 1 and 2, every 3 weeks, at least 6 times.
• Multiple myeloma: 120 to 150 mg/m² on days 1 and 2 together with prednisone 60 mg/m², given intravenously or orally on days 1 to 4, every 4 weeks, at least 3 times.

Dose Adjustments

• Non-haematological toxicity: reductions are based on the worst CTC grade in the previous cycle. A 50% dose reduction is recommended for grade 3 toxicity, and treatment is interrupted for grade 4.
• The individually calculated reduced dose is given on days 1 and 2 of the cycle concerned.

Special Populations

• Hepatic impairment: no adjustment in mild impairment (serum bilirubin below 1.2 mg/dL). A 30% dose reduction is recommended in moderate impairment (bilirubin 1.2 to 3.0 mg/dL). There are no data in severe impairment (above 3.0 mg/dL), where it is contraindicated.
• Renal impairment: no adjustment when creatinine clearance is above 10 mL/min; experience in severe renal impairment is limited.
• Elderly: no evidence that a dose adjustment is needed.
• Children and adolescents: safety and efficacy have not been established, and the available data are not enough for a dose recommendation.

Myelosuppression

Myelosuppression can occur. When it is treatment-related, blood counts (leucocytes, platelets, haemoglobin, neutrophils) are checked at least weekly. The counts needed before treatment starts or resumes are given under Administration and Dosage.

Infections

Serious and fatal infections have occurred, including sepsis, pneumonia and opportunistic infections such as Pneumocystis jirovecii pneumonia, varicella zoster virus and cytomegalovirus. Progressive multifocal leukoencephalopathy, including fatal cases, has been reported, mainly with rituximab or obinutuzumab. Bendamustine can cause prolonged lymphocytopenia (below 600/μL) and low CD4-positive T-cell counts (below 200/μL) for at least 7 to 9 months after treatment, more markedly with rituximab. Pneumocystis jirovecii prophylaxis should be considered if CD4-positive T cells fall below 200/μL. Patients are monitored for respiratory signs and told to report fever, respiratory symptoms or other new signs of infection quickly. Interruption should be considered if infection develops. In patients with new or worsening neurological, cognitive or behavioural signs, progressive multifocal leukoencephalopathy is considered and treatment is interrupted until it is excluded.

Hepatitis B Reactivation

Hepatitis B reactivation has occurred in chronic carriers, sometimes with acute liver failure or death. Patients are tested for hepatitis B infection before treatment. Liver and hepatitis B experts are consulted before treating patients who test positive, and carriers who need treatment are monitored closely during and for several months after it.

Skin Reactions

Skin reactions include rashes, severe skin reactions and bullous exanthema. Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS, some fatal, have been reported. Patients should know the warning signs and seek medical care at once. Reactions may progress and worsen with continued treatment, in which case bendamustine is interrupted or stopped; it is stopped if a severe skin reaction is suspected to be related to it. Non-melanoma skin cancer (basal cell and squamous cell carcinoma) was seen more often in patients treated with bendamustine-containing regimens, so regular skin examination is recommended, especially with risk factors.

Cardiac Disorders

In patients with heart disease, blood potassium is monitored closely and potassium is given if it falls below 3.5 mEq/L; ECGs are performed. Fatal myocardial infarction and heart failure have been reported, and patients with heart disease or a history of it are observed closely.

Tumour Lysis Syndrome

Tumour lysis syndrome usually starts within 48 hours of the first dose and, untreated, can cause renal failure and death. Preventive measures before starting include adequate hydration, close monitoring of blood chemistry (especially potassium and uric acid) and uric acid-lowering agents such as allopurinol and rasburicase.

Infusion Reactions and Anaphylaxis

Infusion reactions were common in trials and usually mild (fever, chills, itching, rash); severe anaphylactic and anaphylactoid reactions occurred only exceptionally. After the first cycle, patients are asked about symptoms suggesting infusion reactions. Antihistamines, antipyretics and corticosteroids should be considered for later cycles in those who reacted before. Patients with grade 3 or worse allergic reactions were usually not treated again.

Nausea, Vomiting and Extravasation

An antiemetic can be given for symptomatic treatment of nausea and vomiting. If extravasation occurs, the injection is stopped at once, the needle is withdrawn after brief aspiration, the tissue is cooled and the arm elevated. It is unclear whether further treatment such as corticosteroids helps.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: bendamustine is teratogenic and mutagenic. Data in pregnant women are insufficient, and non-clinical studies showed embryo-foetal lethality, teratogenicity and genotoxicity. It should not be used in pregnancy unless clearly necessary. If treatment is essential or pregnancy occurs, the patient is told of the risk to the child and closely monitored, and genetic counselling should be considered.
• Contraception: women of childbearing potential must use effective contraception before and during treatment. Men are advised not to father a child during treatment and for 6 months after it, and to seek advice on sperm preservation beforehand because irreversible infertility is possible.
• Breastfeeding: contraindicated; breastfeeding must be stopped during treatment.

Effect on Driving

Bendamustine has a major influence on the ability to drive and use machines. Ataxia, peripheral neuropathy and somnolence have been reported, and patients with these symptoms should avoid potentially dangerous activities such as driving or operating machinery.

The Levact SmPC sets no temperature limit for the unopened vial. Keep the vial in its outer carton to protect it from light. For storage after reconstitution and dilution, see Shelf Life. The powder is supplied in brown type I glass vials (25 mg vials in packs of 5, 10 or 20; 100 mg vials in packs of 5), and not all pack sizes may be marketed.

• Unopened vial: 3 years.
• After opening: the powder must be reconstituted immediately after the vial is opened, and the reconstituted concentrate must be diluted immediately in 0.9% sodium chloride solution.
• Diluted solution: chemically and physically stable for 3.5 hours at 25 °C (60% relative humidity) and for 2 days at 2–8 °C in polyethylene bags. From a microbiological point of view it should be used immediately; otherwise in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx). Bendamustine is given as an intravenous infusion in hospital under the supervision of a physician experienced in chemotherapy, so it is supplied to the hospital or clinic that administers it. The unopened vials need no cold chain.