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BENDAMUSTINE HYDROCHLORIDE ACCORD Powder for concentrate for solution for infusion (2019)

Active ingredients: Bendamustine

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/µl or <75,000/µl, respectively).

Major surgery less than 30 days before start of treatment.

Infections, especially involving leukocytopenia.

Yellow fever vaccination.

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/µl or >100,000/µl, 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). 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 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/μl) 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.

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 should be withheld or discontinued. For severe skin reactions with a suspected relationship to bendamustine hydrochloride treatment should be discontinued.

Cardiac disorders

During treatment with bendamustine hydrochloride the concentration of potassium in the blood of patients with cardiac disorders must be closely monitored and potassium supplement must be given when K+ <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 were 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.

Interaction with other medicinal products and other forms of interaction

No in-vivo interaction studies have been performed.

When Bendamustine is combined with myelosuppressive agents, the effect of Bendamustine 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 Bendamustine.

Combination of Bendamustine 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, the potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir and cimetidine exists.

Paediatric population

Interaction studies have only been performed in adults.

Fertility, pregnancy and lactation

Pregnancy

There are insufficient data from the use of Bendamustine in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo-/fetolethal, teratogenic and genotoxic (see section 5.3). During pregnancy Bendamustine should not be used unless clearly necessary. The mother should be informed about the risk to the foetus. If treatment with Bendamustine 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 counselling should be considered.

Fertility

Women of childbearing potential must use effective methods of contraception both before and during Bendamustine therapy.

Men being treated with Bendamustine 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.

Breast-feeding

It is not known whether bendamustine passes into the breast milk, therefore, Bendamustine is contraindicated during breast-feeding (see section 4.3). Breast-feeding must be discontinued during treatment with Bendamustine.

Effects on ability to drive and use machines

Bendamustine hydrochloride 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 should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.

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.

Table 1. Adverse reactions in patients treated with bendamustine hydrochloride:

Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥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)

Infections and infestations

Very common: Infection NOS*, Including Opportunistic infection ( e.g. Herpes zoster, cytomegalovirus , hepatitis B)

Uncommon: Pneumocystis jirovecii pneumonia

Rare: Sepsis

Very rare: Pneumonia primary atypical

Neoplasma benign, malignant and unspecified (including cyst and polyp)

Common: Tumour lysis syndrome

Uncommon: Myelodysplastic syndrome, acute myeloid leukemia

Blood and lymphatic system disorders

Very common: Leukopenia NOS*, Thrombocytopenia, Lymphopenia

Common: Haemorrhage, Anaemia, Neutropenia

Uncommon: Pancytopenia

Rare: Bone marrow failure

Very rare: Haemolysis

Immune system disorders

Common: Hypersensitivity NOS*

Rare: Anaphylactic reaction, Anaphylactoid reaction

Very rare: Anaphylactic shock

Nervous system disorders

Very common: Headache

Common: Insomnia, Dizziness

Rare: Somnolence, Aphonia

Very rare: Dysgeusia, Paraesthesia, Peripheral sensory neuropathy, Anticholinergic syndrome, Neurological disorders, Ataxia, Encephalitis

Cardiac disorders

Common: Cardiac dysfunction, such as palpitations, angina pectoris, Arrhythmia

Uncommon: Pericardial effusion, Myocardial infarction, Cardiac failure

Very rare: Tachycardia,

Not known: Atrial fibrillation

Vascular disorders

Common: Hypotension, Hypertension

Rare: Acute circulatory failure

Very rare: Phlebitis

Respiratory, thoracic and mediastinal disorders

Common: Pulmonary dysfunction

Very rare: Pulmonary fibrosis

Not known: Pneumonitis, pulmonary alveolar haemorrhage

Gastrointestinal disorders

Very common: Nausea, Vomiting

Common: Diarrhoea, Constipation, Stomatitis

Very rare: Haemorrhagic oesophagitis, Gastrointestinal haemorrhage

Skin and subcutaneous tissue disorders

Common: Alopecia, Skin disorders NOS*, Urticaria

Rare: Erythema, Dermatitis, Pruritus, Maculopapular rash, Hyperhidrosis

Not known: Stevens – Johnson syndrome, Toxic Epidermal Necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Reproductive system and breast disorders

Common: Amenorrhea

Very rare: Infertility

Renal and urinary disorders

Not known: Renal failure

Hepatobiliary disorder

Not known: Hepatic failure

General disorders and administration site conditions

Very common: Mucosal inflammation, Fatigue, Pyrexia

Common: Pain, Chills, Dehydration, Anorexia

Very rare: Multi organ failure

Investigations

Very common: Haemoglobin decrease, Creatinine increase, Urea increase

Common: AST increase, ALT increase, Alkaline phosphatase increase, Bilirubin increase, Hypokalemia

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 been 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 national reporting system Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.