Mianda 25 mg/100 mg Solution
PDF Leaflet Revision Date: 18 July 2020
Clinical Summary
Quick overview from the medicine insert
Indication
First-line treatment for specific leukemias and lymphomas.
Dosage (summary)
100 mg/mu00b2 on days 1 and 2 every 4 weeks for CLL; 90 mg/mu00b2 + rituximab for NHL.
Onset of Action / Duration
Onset: 30 mins, Duration: 4 weeks
Special Populations
- Hepatic impairment
- Renal impairment
- Elderly patients
Pregnancy & Breastfeeding
Contraindicated in pregnancy and breastfeeding.
Key Drug Interactions
- CYP1A2 inhibitors
- Myelosuppressive agents
- Ciclosporin
Contraindications
- Hypersensitivity
- Severe hepatic impairment
- Severe bone marrow suppression
Common side effects
- Leukopenia
- Thrombocytopenia
- Nausea
- Vomiting
Counselling Points
- Avoid pregnancy during treatment
- Monitor for signs of infection
- Seek medical attention for severe skin reactions
Serious warnings
- Myelosuppression
- Infection risk
- Hepatitis B reactivation
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Clinical Particulars
Section 4 of the official insert — extracted exactly as issued, no alterations
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.
- First-line treatment of indolent CD 20 positive non- Hodgkinu2019s lymphoma in combination with rituximab.
- Indolent non- Hodgkinu2019s 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 MIANDA on days 1 and 2; every 4 weeks.
Combination treatment for first-line indolent non- Hodgkinu2019s lymphoma 90 mg/m2 body surface area MIANDA 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- Hodgkinu2019s lymphomas refractory to rituximab 120 mg/m2 body surface area MIANDA on days 1 and 2; every 3 weeks.
Multiple Myeloma 120-150 mg/m2 body surface area MIANDA on days 1 and 2, 60 mg/m2 body surface area prednisone I.V. or orally on days 1 to 4; every 4 weeks.
Hepatic impairment
On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment [serum bilirubin 3,0 mg/dl (51,3 u03bcmol/l )].
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.
Paediatric patients
There is no experience in children and adolescents with MIANDA.
Elderly patients
There is no evidence that dose adjustments are necessary in elderly patients (see section 5.2).
Method of administration
Precautions to be taken before manipulation or handling medicine
When handling MIANDA, 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)
MIANDA is given via intravenous infusion over 30 to 60 minutes. Infusion must be administered under the supervision of a medical practitioner qualified and experienced in the use of chemotherapeutic agents. Poor bone marrow function is related to increased chemotherapy-induced haemotological toxicity. Treatment should not be started if leukocyte and/or platelet values dropped to u02c2 3 x 109/l or u02c2 75 x 109/l, respectively (see section 4.3). Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to u2264 3 x 109/l or u2264 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 u2013 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 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. 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.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients in MIANDA
- Pregnancy and lactation
- Severe hepatic impairment [serum bilirubin > 2,0 mg/dl (34,2 u03bcmol/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 start of treatment
- Infections, especially involving leukocytopenia
- Yellow fever vaccination or any other live attenuated vaccine
- Congenital QT prolongation
- Concomitant medicines causing QT prolongation
4.4 Special warnings and precautions for use
Myelosuppression
Patients treated with MIANDA may 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
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 MIANDA are more susceptible to opportunistic infections. Opportunistic infection such as Pneumocystis jivovecii pneumonia (PJP), varicella zoster virus and cytomegalovirus (CMV) have been reported. Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (u02c2600/u03bcl) and low CD4-positive T-cell (T-helper cell) counts (u02c2200/u03bcl) 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. In case of low CD4-positive T-cell counts (u02c2200/u03bcl) 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 MIANDA 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 MIANDA is commenced.
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 skin 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 (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 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, MIANDA should be withheld or discontinued. For severe skin reactions where a relationship to MIANDA is suspected, treatment should be discontinued.
Cardiac disorders
During treatment with MIANDA the concentration of potassium in the blood must be closely monitored. When serum potassium levels are < 3,5 mEq/l, (3,5 mmol/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 MIANDA 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.
Anaphylaxis
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms 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, MIANDA should be discontinued.
Contraception
Bendamutine 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 MIANDA 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). There are reports of secondary tumours, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukaemia and bronchial carcinoma.
Patients treated with MIANDA may 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
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 MIANDA are more susceptible to opportunistic infections. Opportunistic infection such as Pneumocystis jivovecii pneumonia (PJP), varicella zoster virus and cytomegalovirus (CMV) have been reported. Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (u02c2600/u03bcl) and low CD4-positive T-cell (T-helper cell) counts (u02c2200/u03bcl) 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. In case of low CD4-positive T-cell counts (u02c2200/u03bcl) 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 MIANDA 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 MIANDA is commenced.
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 skin 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 (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 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, MIANDA should be withheld or discontinued. For severe skin reactions where a relationship to MIANDA is suspected, treatment should be discontinued.
Cardiac disorders
During treatment with MIANDA the concentration of potassium in the blood must be closely monitored. When serum potassium levels are < 3,5 mEq/l, (3,5 mmol/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 MIANDA 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.
Anaphylaxis
Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms 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, MIANDA should be discontinued.
Contraception
Bendamutine 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 MIANDA 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). There are 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 MIANDA is combined with myelosuppressive agents, the effect of MIANDA and/or the co-administered medicinal products on the bone marrow may be potentiated. Any treatment reducing the patientu2019s performance status or impairing bone marrow function can increase the toxicity of MIANDA. Combination of MIANDA 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 exists.
4.6 Fertility, Pregnancy and lactation
Pregnancy
There are no adequate data from the use of MIANDA in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo/fetolethal, teratogenic and genotoxic. Therefore, MIANDA is contraindicated during pregnancy (see section 4.3).
Women of childbearing potential/contraception
Women of childbearing potential must use effective methods of contraception both before and during MIANDA therapy.
Breast-feeding
It is not known whether bendamustine passes into the breast milk, therefore it is contraindicated during breast-feeding (see section 4.3). Breast-feeding must be discontinued during treatment with MIANDA.
Fertility
Men being treated with MIANDA 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 MIANDA.
There are no adequate data from the use of MIANDA in pregnant women. In nonclinical studies bendamustine hydrochloride was embryo/fetolethal, teratogenic and genotoxic. Therefore, MIANDA is contraindicated during pregnancy (see section 4.3).
Women of childbearing potential/contraception
Women of childbearing potential must use effective methods of contraception both before and during MIANDA therapy.
Breast-feeding
It is not known whether bendamustine passes into the breast milk, therefore it is contraindicated during breast-feeding (see section 4.3). Breast-feeding must be discontinued during treatment with MIANDA.
Fertility
Men being treated with MIANDA 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 MIANDA.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, 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.
4.8 Undesirable effects
The most frequent side effects with MIANDA are haematological adverse reactions (leukopenia, thrombocytopenia), dermatologic toxicities (allergic reactions), constitutional symptoms (fever), gastrointestinal symptoms (nausea, vomiting).
Infections and infestations:
Frequent: Infection (not otherwise specified), opportunistic infection (including Herpes zoster, cytomegalovirus, hepatitis B)
Less frequent: Pneumocystis jiroveci pneumonia, septicaemia, primary atypical pneumonia, tuberculosis (TB)
Neoplasms benign and malignant:
Frequent: Tumour lysis syndrome
Less frequent: Myelodysplastic syndrome, acute myeloid leukaemia
Blood and lymphatic system disorders:
Frequent: Leukopenia (not otherwise specified), thrombocytopenia, haemorrhage, anaemia, neutropenia, lymphopenia
Less frequent: Pancytopenia, bone marrow failure, haemolysis
Immune system disorders:
Frequent: Hypersensitivity (not otherwise specified)
Less frequent: Anaphylactic reaction, anaphylactoid reaction, anaphylactic shock
Metabolism and nutrition disorders:
Frequent: Tumour lysis syndrome
Nervous system disorders:
Frequent: Headache, insomnia, dizziness
Less frequent: Somnolence, aphonia, dysgeusia, paraesthesia, peripheral sensory neuropathy, 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: Pulmonary fibrosis
Frequency unknown: Pneumonitis, pulmonary alveolar haemorrhage
Gastrointestinal disorders:
Frequent: Nausea, vomiting, diarrhoea, constipation, stomatitis
Less frequent: Haemorrhagic oesophagitis, gastrointestinal haemorrhage
Hepato-biliary disorders:
Frequency unknown: Hepatic failure
Skin and subcutaneous tissue disorders:
Frequent: Alopecia, skin disorders (not otherwise specified)
Less frequent: Erythema, dermatitis, pruritus, maculopapular rash, hyperhidrosis
Frequency unknown: Stevens u2013 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
Less frequent: Infertility
General disorders and administration site conditions:
Frequent: Mucosal inflammation, fatigue, pyrexia, pain, chills, dehydration, anorexia
Less frequent: Multi organ failure
Investigations:
Frequent: Haemoglobin decrease, creatinine increase, urea increase, AST increase, ALT increase, alkaline phosphatase increase, bilirubin increase, hypokalaemia.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8
4.9 Overdose
After application of a 30 min infusion of bendamustine once every 3 weeks the maximum tolerated dose (MTD) was 280 mg/mu00b2. Cardiac events of CTC 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 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 and its metabolites are dialyzable to a small extent.
