Consumer medicine information

Ribomustin

Bendamustine hydrochloride

BRAND INFORMATION

Brand name

Ribomustin

Active ingredient

Bendamustine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ribomustin.

What is in this leaflet

This leaflet answers some common questions about RIBOMUSTIN powder for injection. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given RIBOMUSTIN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet while being treated. You may need to read it again.

What RIBOMUSTIN is used for

RIBOMUSTIN belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines. These medicines are used to kill cancer cells.

RIBOMUSTIN is used for the treatment of certain types of cancer.

RIBOMUSTIN is used alone (monotherapy) or in combination with other medicines for the treatment of the following forms of cancer:

  • Chronic lymphocytic leukaemia;
  • Indolent, Stage III-IV Non-Hodgkin's Lymphoma and Stage III-IV Mantle Cell Lymphoma. It is prescribed for patients who have not been previously treated.
  • Indolent Non-Hodgkins Lymphoma. It is prescribed for patients who have received one or more prior treatment and whose cancer is still progressing.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you are given RIBOMUSTIN

When you must not use it

Do not use RIBOMUSTIN if you:

  • Are hypersensitive (allergic) to the active substance, bendamustine hydrochloride or any of the other ingredients listed at the end of this leaflet;
  • Are breastfeeding;
  • Have severe liver dysfunction (damage to the functional cells of the liver);
  • Have yellowing of the skin or whites of the eyes caused by liver or blood problems (jaundice);
  • Have severely disturbed bone marrow function (bone marrow depression) and serious changes in your number of white blood cells and platelets in the blood;
  • Have had major surgical operations less than 30 days before starting treatment;
  • Have an infection, especially one accompanied by a reduction in white blood cells (leukocytopaenia);
  • In combination with yellow fever vaccines.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not use this medicine if you are pregnant. Like most medicines used to treat cancer, RIBOMUSTIN is not recommended for use during pregnancy.

Do not breast-feed if you are using this medicine.

Before you start to use it

Tell your doctor if you have or have had any of the following medical conditions:

  • reduced capability of the bone marrow to replace blood cells
  • infections, including fever or lung symptoms
  • skin reaction. The reaction may increase in severity
  • heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms)
  • hepatitis B infection
  • severe allergic or hypersensitivity reactions. You should pay attention to infusion reactions after your first cycle of RIBOMUSTIN therapy.

Women of childbearing potential must use effective methods of contraception both before and during RIBOMUSTIN therapy. Men receiving treatment with RIBOMUSTIN are advised not to conceive a child during treatment for up to 6 months afterwards. Before starting treatment, you should seek advice on storing sperm because of the possibility of permanent infertility.

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.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start taking RIBOMUSTIN.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are taking any of the following:

  • medicines that may result in excessive immunosuppression, such as cyclosporine or tacrolimus.
  • fluvoxamine, medicines used to treat depression.
  • ciprofloxacin and aciclovir, medicines use to treat infections.
  • cimetidine, a medicine used to treat duodenal, gastric ulcers.
  • viral vaccination.
  • medicines that inhibit the formation of blood in the bone marrow.

These medicines may be affected by RIBOMUSTIN or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How RIBOMUSTIN is given

Your treatment with RIBOMUSTIN will take place in a specialised medical unit, under the supervision of a doctor experienced in the use of cytotoxic medicinal products.

Treatment should not be started if your white blood cells (leukocytes) have fallen to counts below 3,000 cells/µL and/or your blood platelets have fallen to counts below 75,000 cells/µL. Your doctor will determine these values at regular intervals.

How much is given

Your doctor will decide what dose you will receive. The dose will be calculated from your height and weight. It will also depend on factors such as kidney function, liver function and other medicines you are being given.

Dose for Chronic Lymphocytic Leukaemia:

  • 100mg per square metre of your body surface area
  • Cycle should be repeated after 4 weeks up to 6 times.

Dose for progressing Non-Hodgkin's Lymphoma:

  • 120mg per square metre of your body surface area on days 1 and 2
  • Cycle should be repeated after 3 weeks up to 6 times

Dose for previously not treated indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma:

  • 90mg per square metre on days 1 and 2
  • Cycle should be repeated after 4 weeks up to 6 cycles.
  • Your doctor may change the dose during treatment depending on your response.
  • Ask your doctor if you want to know more about the dose of RIBOMUSTIN you receive.

How it is given

RIBOMUSTIN will be dissolved in sterile normal sodium chloride (salt) solution for injection.

RIBOMUSTIN is administered into a vein over 30-60 minutes in various dosages, either alone (monotherapy) or in combination with other medicines.

How long it is given

There is no time limit laid down as a general rule for treatment with RIBOMUSTIN. Duration of treatment depends on disease and response to treatment.

What do I do if I receive too much? (overdose)

As RIBOMUSTIN is given to you under supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience side effects after being given RIBOMUSTIN, tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital. You may need urgent medical attention.

While you are using RIBOMUSTIN

Things you must do

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some blood, urine or other tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Keep follow-up appointments with your doctor. It is important to have your follow-up doses of RIBOMUSTIN at the appropriate times to get the best effects from your treatment.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking RIBOMUSTIN.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

RIBOMUSTIN can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain.
  • Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutter.

Things to be careful of

Be careful driving or operating machinery until you know how RIBOMUSTIN affects you. This medicine may cause sleepiness, dizziness, lack of coordination or fatigue in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

Like all medicines, RIBOMUSTIN can have side effects. Some of these effects may be serious. However, there may be ways to reduce the discomfort of these effects. You may need medical treatment if you get some of the side effects.

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being treated with RIBOMUSTIN.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Low counts of white blood cells; decrease in the red pigment of the blood (haemoglobin); low counts platelets; decreased number of red blood cells (anaemia)
  • Infections
  • Feeling sick (nausea); vomiting; fatigue; chills, fever, headache or cough
  • Mucosal inflammation
  • Increased blood level of creatinine, glucose or urea
  • Bleeding
  • Hypersensitivity reactions such as allergic inflammation of the skin (dermatitis), nettle rash (urticaria)
  • A rise in liver enzymes AST/ALT
  • A rise in bile pigment
  • A rise in the enzyme alkaline phosphatase
  • Low potassium, sodium or calcium blood levels
  • Disturbed function of the heart; disturbed heart rhythms (arrhythmia)
  • Low or high blood pressure
  • Diarrhoea; constipation, or stomach pain
  • Sore mouth
  • Loss of appetite or weight loss
  • Hair loss
  • Missed periods (amenorrhoea)
  • Insomnia, anxiety, or depression
  • Dehydration including excessive thirst and urine production

Tell your doctor as soon as possible if you notice any of the following:

  • Infection of the blood (sepsis)
  • Severe allergic hypersensitivity reactions (anaphylactic reactions); signs similar to anaphylactic reactions (anaphylactoid reactions)
  • Drowsiness
  • Loss of voice (aphonia)
  • Acute circulatory collapse
  • Reddening of the skin (erythema); inflammation of the skin (dermatitis); itching; skin rash
  • Excessive sweating

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • Pneumonia (primary atypical inflammation of the lungs)
  • Break-down of red blood cell
  • Anaphylactic shock (rapid decrease in blood pressure sometimes with skin reactions rash)
  • Disturbed sense of taste; altered sensations
  • Feeling unwell; pain in the limbs
  • Anticholinergic syndrome (disease of the nervous system); neurological disorders
  • Ataxia (lack of coordination)
  • Inflammation of the brain; inflammation of the veins
  • Increased heart rate; heart attack; chest pain; heart failure
  • Formation of tissue in the lungs (fibrosis of the lungs)
  • Bleeding inflammation of the gullet; bleeding stomach
  • Infertility
  • Multiple organ failure.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After using RIBOMUSTIN

Storage

RIBOMUSTIN should be kept in a cool dry place, protected from light, where temperature stays below 25°C.

Product Description

What it looks like

RIBOMUSTIN is a white, microcrystalline powder in a brown glass vial with rubber stopper and an aluminium flip-off cap.

Each pack contains one single-use vial.

Ingredients

Active ingredient:

  • Bendamustine hydrochloride 25mg
  • Bendamustine hydrochloride 100mg

Other ingredients: mannitol.

Sponsor

JANSSEN-CILAG PTY LTD
1-5 Khartoum Rd
Macquarie Park NSW 2113
Telephone: 1800 226 334

NZ Office: Auckland, New Zealand
Telephone: 0800 800 806

Registration Numbers

RIBOMUSTIN 25mg vial: AUST R 211685

RIBOMUSTIN 100mg vial: AUST R 211684

This leaflet was prepared in September 2022

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Ribomustin

Active ingredient

Bendamustine hydrochloride

Schedule

S4

 

1 Name of Medicine

Bendamustine hydrochloride.

2 Qualitative and Quantitative Composition

Ribomustin contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent.
Bendamustine is soluble in water when at room temperature. It is administered by intravenous infusion after reconstitution with 10 mL (for the 25 mg vial) or 40 mL (for the 100 mg vial) water for injection and further dilution with physiological saline (0.9%).

Ribomustin bendamustine hydrochloride 25 mg powder for injection vial.

Each 25 mg vial contains 25 mg of bendamustine hydrochloride (equivalent to 22.7 mg bendamustine) and 30 mg of mannitol.

Ribomustin bendamustine hydrochloride 100 mg powder for injection vial.

Each 100 mg vial contains 100 mg of bendamustine hydrochloride (equivalent to 90.8 bendamustine) and 120 mg of mannitol. The pH of the reconstituted solution is 2.5 - 3.5.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection, for intravenous infusion.
Ribomustin is a white, microcrystalline lyophilisate powder for concentrate for solution for infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

First line treatment of chronic lymphocytic leukaemia (Binet stage B or C). Efficacy relative to first line therapies other than chlorambucil has not been established.
Previously untreated indolent CD20-positive, stage III-IV non-Hodgkin's lymphoma, in combination with rituximab.
Previously untreated CD20-positive, stage III-IV mantle cell lymphoma in combination with rituximab, in patients ineligible for autologous stem cell transplantation.
Relapsed/ refractory indolent non-Hodgkin's lymphoma.

4.2 Dose and Method of Administration

For intravenous infusion over 30 - 60 minutes (see Section 4.2 Dose and Method of Administration, Special precautions for disposal and handling).
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 should not be started if leukocyte and/or platelet values drop to < 3 x 109/L or < 75 x 109/L, respectively (see Section 4.4 Special Warnings and Precautions for Use, Myelosuppression).

Monotherapy for chronic lymphocytic leukaemia.

100 mg/m2 body surface area bendamustine hydrochloride on days 1 and 2; every 4 weeks, for up to 6 cycles.

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 to 8 cycles (maximum 8 cycles).

Combination therapy with rituximab for first line non-Hodgkin's lymphoma and mantle cell lymphoma.

90 mg/m2 on days 1 and 2 of a 4-week cycle for up to 6 cycles.
Treatment should be terminated or delayed if leukocyte and/or platelet values dropped to < 3 x 109/L or < 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 3-5 weeks.
During therapy free intervals strict monitoring of the blood count is recommended (see Section 4.4 Special Warnings and Precautions for Use).
In case of nonhaematological 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 the toxicity resolves and the previous dose is tolerated, the reduced dose may be increased again.
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.
The powder for concentrate for solution for infusion has to be reconstituted with water for injection, diluted with sodium chloride 9 mg/mL (0.9%) solution for injection and then administered by intravenous infusion. Aseptic technique is to be used.

1. Reconstitution.

Reconstitute each vial of Ribomustin containing 25 mg bendamustine hydrochloride in 10 mL water for injection by shaking.
Reconstitute each vial of Ribomustin containing 100 mg bendamustine hydrochloride in 40 mL water for injection by shaking.
The reconstituted concentrate contains 2.5 mg bendamustine hydrochloride per mL and appears as a clear colourless solution.
No overfill is included.

2. Dilution.

As soon as a clear solution is obtained (usually after 5-10 minutes) dilute the total recommended dose of Ribomustin immediately with 0.9% NaCl solution to produce a final volume of about 500 mL.
Ribomustin must be diluted with 0.9% NaCl solution and not with any other injectable solution.

3. Administration.

The solution is administered by intravenous infusion over 30-60 min.

Hepatic impairment.

On the basis of pharmacokinetic data, no dose adjustment is necessary in patients with mild hepatic impairment (serum bilirubin < 1.2 mg/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 Contraindications).

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 bendamustine.

Elderly patients.

There is no evidence that dose adjustments are necessary in elderly patients.

Special precautions for disposal and handling.

When handling Ribomustin, 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.
The product is for single use in one patient only. Discard any residue. Any unused product or waste material should be disposed of in accordance with local requirements.

4.3 Contraindications

Ribomustin is contraindicated in patients with:
Hypersensitivity to the active substance or to any of the excipients.
Severe hepatic impairment (serum bilirubin > 3.0 mg/dL).
Jaundice.
Severe bone marrow suppression and severe blood count alteration (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 leukocytopaenia.
Yellow fever vaccination.
Ribomustin is also contraindicated during breastfeeding.

4.4 Special Warnings and Precautions for Use

When considering combination treatment with rituximab, please consult the product information for rituximab and consider this in conjunction with the information provided below.

Myelosuppression.

Patients treated with Ribomustin may experience bone marrow failure. In the event of treatment related myelosuppression, leukocytes, platelets, haemoglobin, and neutrophils must be monitored at least weekly. Treatment-related myelosuppression may require dose adjustment and/or dose delays.
Treatment with bendamustine hydrochloride may cause prolonged lymphocytopenia (< 0.6 x 109/L) and low CD4-positive T-cell (T-helper cell) counts (< 0.2 x 109/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.
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. Treatment should not be started if leukocyte and/or platelet values drop to < 3 x 109/L or < 75 x 109/L, respectively.
Ribomustin should not be used during severe bone marrow suppression and severe blood count alterations (see Section 4.2 Dose and Method of Administration).

Infections.

Serious and fatal infections, including fatal sepsis, have occurred with bendamustine treatment. These infections included bacterial (pneumonia) and opportunistic infections such as Pneumocystis jirovecii Pneumonia (PJP), Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), and progressive multifocal leukoencephalopathy (John Cunningham virus).
Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of bendamustine mainly in combination with rituximab or obinutuzumab.
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 (< 0.2 x 109/L), Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be considered. All patients should be monitored for respiratory signs and symptoms throughout treatment. 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.

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. For patients with hepatitis B serology indicative of prior infection, a liver disease expert should be consulted before the start of treatment and the patient should be monitored and managed following local medical standards to prevent hepatitis B reactivation. Monitoring should continue for several months following termination of therapy.

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), some fatal, have also been reported. Some events of SJS and TEN occurred when bendamustine hydrochloride was administered concomitantly with allopurinol or when bendamustine hydrochloride was given in combination with other anticancer agents. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of bendamustine hydrochloride in combination with rituximab. 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. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are progressive, Ribomustin should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine hydrochloride is suspected, treatment should be discontinued.

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.

Patients with cardiac disorders.

During treatment with Ribomustin the concentration of potassium in the blood 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 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 associated with Ribomustin treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of Ribomustin and, without intervention, may lead to acute renal failure and death. Preventive measures include adequate volume status, close monitoring of blood chemistry, particularly potassium and uric acid levels. The use of allopurinol during the first one to two weeks of Ribomustin therapy can be considered but not necessarily as standard. However, there have been a few cases of Stevens-Johnson syndrome and toxic necrolysis reported when bendamustine and allopurinol are concomitantly administered.

Infusion reactions and anaphylaxis.

Infusion reactions to bendamustine hydrochloride have occurred 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 rechallenged.

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.

Other malignancies.

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.

Use in the elderly.

No data available.

Paediatric use.

There is no experience in children and adolescents with Ribomustin.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No in vivo interaction studies have been performed.
When Ribomustin is combined with myelosuppressive agents, the effect of Ribomustin and/or the coadministered 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 Ribomustin.
Combination of Ribomustin 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 metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme (see Section 5.2 Pharmacokinetic Properties). Therefore, potential for interaction with CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, aciclovir, cimetidine exists. Based on in vitro data, bendamustine is not likely to inhibit metabolism via CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.
The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport. Inhibitors of these transporters may increase the plasma concentration of bendamustine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility studies have been conducted in animals. However, results from toxicity studies in rats and dogs indicate the potential of bendamustine to impair male reproductive function and fertility. Testicular atrophy was seen in dogs that received ≥ 1.65 mg/kg IV bendamustine, while at higher doses (6.6 mg/kg IV to dogs and ≥ 40 mg/kg/day PO to rats), reduced spermatogenesis was seen. Estimated exposures at the no-effect level were subclinical in dogs and similar to the clinical exposure in rats. Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Ribomustin.
Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacities.
(Category D)
There are insufficient data from the use of Ribomustin in pregnant women. Bendamustine was shown to be embryo/fetolethal and teratogenic in animal studies. Single intraperitoneal doses of bendamustine to pregnant mice (210 mg/m2) and rats (60 mg/m2) during the period of organogenesis, resulted in embryofoetal lethality, decreased foetal bodyweights and an increase in foetal skeletal and visceral malformations (cleft palate, turricephaly, rib malformations and spinal deformities, and hepatic or intestinal ectopia).
During pregnancy Ribomustin should not be used unless clearly necessary. The mother should be informed about the risk to the foetus. If treatment with Ribomustin 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.
Women of childbearing potential must use effective methods of contraception both before and during Ribomustin therapy.
Men being treated with Ribomustin 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 Ribomustin.
 It is not known whether bendamustine passes into the breast milk, therefore, bendamustine is contraindicated during breastfeeding (see Section 4.3 Contraindications). Breastfeeding must be discontinued during treatment with bendamustine.

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, somnolence has been reported during treatment with Ribomustin (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving and using machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials data.

Chronic lymphocytic lymphoma.

The following tables describe the safety results reported in study 02CLLIII of 161 previously untreated patients with Binet stage B or C CLL requiring treatment. See Table 1.
A total of 50 patients had 60 serious adverse events. Most frequently occurring serious adverse events in the bendamustine group were hypersensitivity and pneumonia (each with 3 patients) and anaemia, vomiting, pyrexia and tumour lysis syndrome (each with 2 patients). Most frequent documented serious adverse event in the chlorambucil group was herpes zoster (with 2 patients). All other events were documented only once by patient. See Table 2.
Number of adverse events possible, probable or definite related to the study medication (including missing relationship) was higher in the bendamustine arm than in the chlorambucil arm. Especially blood and lymphatic system disorders, gastrointestinal disorders and pyrexia occurred more frequently under bendamustine than under chlorambucil.
See Table 3.
The most frequent adverse reactions leading to study withdrawal for patients receiving Ribomustin were hypersensitivity (2%) and pyrexia (1%).

Results from the NHL1-2003 clinical trial in patients with previously untreated advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma.

Tables 4 and 5 describe safety data from the NHL1-2003 study with previously untreated advanced indolent NHL who received Ribomustin IV (90 mg/m2) in combination with rituximab (375 mg/m2).
Adverse event data provided below is based on published data and is therefore limited in nature.

Relapsed/ refractory non-Hodgkin's lymphoma.

Table 6 lists adverse events occurring in at least 5% of patients in study SDX-105-03.
The data described below reflect exposure to Ribomustin in 176 patients with indolent B cell NHL treated in two single arm studies (SDX-105-03 and SDX-105-01).
The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 7.
Haematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 8. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in > 1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycaemia (3%), elevated creatinine (2%), hyponatraemia (2%), and hypocalcaemia (2%).
In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving Ribomustin. The most common serious adverse reactions occurring in 5% of patients were febrile neutropaenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, pneumonitis, pulmonary alveolar haemorrhage, and myelodysplastic syndrome.
Serious drug related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumour lysis syndrome and infusion reactions (see Section 4.4 Special Warnings and Precautions for Use). Adverse reactions occurring less frequently but possibly related to Ribomustin treatment were haemolysis, dysgeusia/ taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

Postmarketing experience.

The following adverse reactions have been identified during postapproval use of Ribomustin (Table 9).
The frequencies are provided according to the following convention:
Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1000 and < 1/100; Rare ≥ 1/10,000 and < 1/1000; Very rare < 1/10,000, including isolated reports.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Increases in alanine aminotransferase; aspartate aminotransferase; blood bilirubin and blood urea levels have been reported. Somnolence, atrial fibrillations and palpitations have also been reported.
Skin reactions including Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (combination therapy with rituximab), some fatal, have been reported with the use of bendamustine hydrochloride (see Section 4.4 Special Warnings and Precautions for Use, Skin reactions and Tumour lysis syndrome). In addition, a few cases of hepatitis B reactivation resulting in hepatic failure have been reported in patients treated with bendamustine. Pancytopenia, headache, dizziness, opportunistic infection (e.g. herpes zoster, cytomegalovirus, Pneumocystis jirovecii pneumonia), bone marrow failure, hepatic failure, renal failure and nephrogenic diabetes insipidus have also been reported in patients treated with bendamustine.
The CD4/CD8 ratio may be reduced. A reduction of the lymphocyte count was seen. In immunosuppressed patients, the risk of infection (e.g. with herpes zoster) may be increased.
There have been isolated reports of necrosis after accidental extra-vascular administration, 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 suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum single dose of bendamustine received in clinical studies was 280 mg/m2 body surface area.
Three out of the four patients treated with 280 mg/m2 experienced ECG changes which were regarded as dose limiting toxicities on days 7 and 21. These changes included prolonged QT, sinus tachycardia (1 patient), displaced ST and T waves (2 patients) and left interior fascicle block (1 patient).
There is no specific antidote for bendamustine overdosage. Supportive therapy should be given when needed.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bendamustine hydrochloride is an alkylating antitumour agent with unique activity. The antineoplastic and cytocidal 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. Bendamustine is active against both quiescent and dividing cells.
The active substance revealed no or very low cross resistance in human tumour cell lines with different resistance mechanisms.
The exact mechanism of action of bendamustine remains unknown.

Clinical trials.

Chronic lymphocytic lymphoma.

The safety and efficacy of Ribomustin were evaluated in an open label, randomised, controlled multicenter trial (02CLLIII) comparing Ribomustin to chlorambucil. The trial was conducted in 319 previously untreated patients with Binet stage B or C CLL requiring treatment. Need to treat criteria included hematopoietic insufficiency, B symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune haemolytic anaemia or autoimmune thrombocytopenia, Richter's syndrome, or transformation to prolymphocytic leukaemia were excluded from the study.
The patient populations in the Ribomustin and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (72% vs. 71% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (77% vs. 78%), enlarged liver (49% vs. 45%), hypercellular bone marrow (80% vs. 73%), lymphocyte count (mean 68.9 x 109/L vs. 62.4 x 109/L). Ninety percent of patients in both treatment groups had immunophenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both). Most of the patients had WHO performance status (PS) 0 (70% vs. 65%). PS 1 was documented in 27% vs. 29% patients.
Patients were randomly assigned to receive either Ribomustin at 100 mg/m2, administered intravenously over a period of 30 minutes on days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca's normal weight) administered orally on days 1 and 15 of each 28 day cycle.
The primary efficacy endpoints of overall response rate and progression free survival were calculated using a prespecified algorithm based on NCI working group criteria for CLL.
The results of this open label randomised study demonstrated a higher rate of overall response and a longer progression free survival for Ribomustin compared to chlorambucil. Survival data are not mature.
An ICRA (Independent Committee for Response Assessment) review was completed 12 months after the last patient completed treatment in the study. The results from this follow-up ITT analysis are presented in Table 10.
Complete response is lower than noted in Table 10, for both bendamustine and chlorambucil, if there is a requirement for imaging to confirm lymph nodes ≤ 1.5 cm.
Progression free survival based upon the Independent Committee Response Assessment (ICRA) criteria by treatment group in the follow-up report (ITT analysis) in study 02CLLIII is shown in Figure 1.

Previously untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma (MCL).

The safety and efficacy of Ribomustin in previously untreated advanced indolent NHL and MCL have been assessed in a phase III trial.
The NHL1-2003 study is a prospective phase III, multicentre, randomised (1:1), noninferiority, open label clinical study of 549 patients, conducted to determine that Ribomustin (90 mg/m2) in combination with rituximab 375 mg/m2 is noninferior to CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg/day for 5 days) plus rituximab 375 mg/m2. Rituximab was administered in both treatment arms on day 1 of each cycle. Treatment was administered for a maximum of 6 cycles. Baseline demographics and patient characteristics are summarized in Table 11.
Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m2 on days 1 and 2 of a 4 week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m2 on day 1 of each cycle. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle cell lymphoma. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression free survival, with a noninferiority margin of 10%.
At median follow-up of 45 months (IQR 25-57), median progression free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs. 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p < 0.0001).
A significant benefit for progression free survival was shown with B-R vs. R-CHOP for all histological subtypes except for marginal zone lymphoma (see Figure 2).
The improvement in progression free survival with B-R was independent of age, concentration of lactate dehydrogenase (LDH), and FLIPI score (see Table 12). Overall survival did not differ between the two treatment groups.
The rate of overall response did not differ between the treatment groups (93% for B-R vs. 91% for R-CHOP); however the rate of complete response was significantly increased in patients in the B-R group (104 [40%] vs. 76 [30%]; p = 0.021).

Relapsed/ refractory NHL.

The efficacy of Ribomustin was evaluated in a single arm study (SDX-105-03) of 100 patients with indolent B cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received Ribomustin intravenously at a dose of 120 mg/m2, on days 1 and 2 of a 21 day treatment cycle. Patients were treated for up to 8 cycles.
The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumour subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.
Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 13.
Progression free survival (PFS), a secondary endpoint in this study, was comparable across all patient groups defined by baseline characteristics (see Table 14). The median PFS was 72 weeks in patients without previous alkylator therapy, and 51 weeks in patients who were sensitive to the previous alkylator therapy or chemotherapy. In the patients who had received previous radioimmunotherapy, the PFS was 53 weeks. Disease characteristics at baseline (FLIPI risk category, number of lymph nodal sites, or bulky disease) did not markedly affect duration of PFS.

5.2 Pharmacokinetic Properties

Absorption.

Peak plasma concentrations of bendamustine occurred typically at the completion of 30 or 60 minute infusions, after which the drug was rapidly cleared from the plasma. After a single dose of bendamustine 120 mg/m2 infused over 60 minutes in a clinical study in patients with indolent NHL refractory to rituximab, the drug was eliminated from the plasma in a generally triphasic manner characterized by an initial rapid distribution phase, a slower secondary phase, and a longer terminal phase. In this study, the mean ± SD Cmax was 5.6 ± 2.4 microgram/mL and the mean ± SD AUCinf was 7.2 ± 3.8 microgram.hr/mL. There were no formal dose proportionality studies in humans with bendamustine administered by I.V. infusion.

Distribution.

Following 30 min I.V. infusion the central volume of distribution was 19.3 L. Under steady-state conditions following 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).

Metabolism.

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 CYP1A2, CYP2C9/10, CYP2D6, CYP2E1 and CYP3A4.

Excretion.

The elimination half-life t1/2β after 30 min I.V. infusion of 120 mg/m2 to 12 subjects was 28.2 minutes. 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. Mean recovery of total radioactivity in cancer patients following intravenous infusion of [14C]-bendamustine hydrochloride was approximately 76% of the radiochemical dose when collected up to day 8 (168 hrs postdose). Approximately half (45.5%) of the dose was recovered in the urine and approximately a quarter (25.2%) of the dose was recovered in the faeces.
Urinary excretion was confirmed as a relatively minor pathway of elimination of unmodified bendamustine, with only approximately 3.3% of the dose recovered in the urine as the parent compound. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.

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, t1/2β, volume of distribution and clearance.

Hepatic impairment.

In patients with 30-70% tumour involvement 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, t1/2β, volume of distribution and clearance. AUC and total body clearance of bendamustine correlate inversely with serum bilirubin. Patients with moderate to severe hepatic impairment, whether measured by tumour involvement and serum bilirubin or Child-Pugh classification have not been assessed.

Elderly subjects.

Subjects up to 84 years of age [< 65 yrs (n = 30); 65-75 yrs (n = 14) and > 75 yrs (n = 5)] were included in pharmacokinetic studies. Higher age does not influence the pharmacokinetics of bendamustine.

5.3 Preclinical Safety Data

Genotoxicity.

Bendamustine was mutagenic in the bacterial mutation assay and clastogenic in in vitro (human lymphocytes) and in vivo (rat micronucleus test) studies.

Carcinogenicity.

After 4 daily intraperitoneal or oral doses of bendamustine to female mice, drug-related tumours appeared during the lifetime follow-up period, peritoneal sarcoma in mice that received intraperitoneal doses (≥ 50 mg/kg/day or 150 mg/m2), and pulmonary adenomas and mammary carcinomas in mice that received oral doses (250 mg/kg/day).

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Unopened vials.

Store below 25°C. Keep the container in the outer carton in order to protect from light.
The powder should be reconstituted immediately after opening of the vial. The reconstituted concentrate should be diluted immediately with 0.9% sodium chloride solution.

Reconstituted solution.

To reduce microbiological hazard, use as soon as possible after reconstitution/preparation. If storage is necessary, hold at not more than 3.5 hours at 25°C or at 2-8°C for not more than 24 hours. 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.

6.5 Nature and Contents of Container

Ribomustin is supplied in Type I brown glass vials of 26 mL or 60 mL with rubber stopper and an aluminium flip-off cap.
26 mL-vials contain 25 mg bendamustine hydrochloride; supplied in cartons containing 1 vial.
60 mL-vials contain 100 mg bendamustine hydrochloride; supplied in cartons containing 1 vial.
The vials are for single use only.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


C16H21Cl2N3O2.HCl. MW: 394.7.
The chemical name for bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2chloroethyl)amino]-1 methyl-, monohydrochloride.

CAS number.

3543-75-7.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes