Ribocedal^®

• First-line treatment of chronic lymphocytic leukaemia (Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate.
• Indolent non-Hodgkin’s lymphomas as monotherapy in patients who have progressed during or within 6 months following treatment with rituximab or a rituximab containing regimen.

Front line treatment of multiple myeloma (Durie-Salmon stage II with progress or stage III) in combination with prednisone for patients older than 65 years who are not eligible for autologous stem cell transplantation and who have clinical neuropathy at time of diagnosis precluding the use of thalidomide or bortezomib containing treatment.

• Hypersensitivity to the active substance or to any of the excipients such as Mannitol.
• During breastfeeding
• 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

Myelosuppression

Patients treated with Ribocedal^® 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 Ribocedal^®, including bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP), varicella zoster virus (VZV) and cytomegalovirus (CMV). Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reported following the use of bendamustine mainly in combination with rituximab or obinutuzumab. Treatment with Ribocedal^® 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 Ribocedal^® is combined with rituximab. Patients with lymphopenia and low CD4-positive T-cell count following treatment with Ribocedal^® are more susceptible to (opportunistic) infections. In case of low CD4-positive T-cell counts (< 200 µ/l) 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 Ribocedal^® 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 Ribocedal^®. 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 Ribocedal^® should be closely monitored for signs and symptoms of active HBV infection throughout therapy and 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), 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. When skin reactions are progressive, Ribocedal^® should be withheld or discontinued. For severe skin reactions with suspected relationship to Ribocedal^® , 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.

Cardiac disorders

During treatment with Ribocedal^® 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 hydrochloride treatment has been reported in patients in clinical trials. The onset tends to be within 48 hours of the first dose of Ribocedal^® and, without intervention, may lead to acute renal failure and death. Preventive measures such as adequate hydration and 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 Ribocedal^® 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

Ribocedal^® 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 Ribocedal^® 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.

Ribocedal^® must only be administered under the supervision of a physician qualified in the use of anti­cancer chemotherapy.

Dosage:

Monotherapy for chronic lymphocytic leukaemia

100 mg/m² body surface area Ribocedal^®on days 1 and 2; every 4 weeks.

Monotherapy for indolent non-Hodgkin’s lymphomas refractory to rituximab

120 mg/m² body surface area Ribocedal^®on days 1 and 2; every 3 weeks.

Multiple myeloma

120 – 150 mg/m² body surface area Ribocedal^® on days 1 and 2, 60 mg/m² body surface area prednisone i.v. or per os on days 1 to 4; every 4 weeks.

Poor bone marrow function is related to increased chemotherapy-induced haematological toxicity. Treatment should not be started if leukocyte and/or platelet values have dropped to < 3,000/µl or < 75,000/µl, respectively.

Treatment should be terminated or delayed if leukocyte and/or platelet values have dropped to < 3,000/µl or < 75,000/µl, respectively. Treatment can be continued after leukocyte values have increased to > 4,000/µl and platelet values to > 100,000/µl.

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.

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.

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).

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 population

The safety and efficacy of Ribocedal^® in children have not yet been established. Current available data is not sufficient to make a recommendation on posology.

Elderly patients

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

Method of administration

For intravenous infusion over 30 – 60 minutes.

Infusion must be administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.

Precautions to be taken before handling or administering the medicinal product.

Aseptically reconstitute each Bendamustine hydrochloride for Injection vial as follows:

✓ 25 mg Bendamustine hydrochloride for Injection vial: Add 5 mL of only Sterile Water for Injection, USP.

✓100 mg Bendamustine hydrochloride for Injection vial: Add 20 mL of only Sterile Water for Injection, USP

Shake well to yield a clear, colorless to a pale-yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used.

Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 to 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection,

USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects with ALMETRA® may include:

• >10%:

Cardiovascular: Peripheral edema (13%)

Central nervous system: Fatigue (9% to 57%), headache (21%), dizziness (14%), chills (6% to 14%), insomnia (13%)

Dermatologic: Skin rash (8% to 16%)

Endocrine & metabolic: Weight loss (7% to 18%), dehydration (14%)

Gastrointestinal: Nausea (20% to 75%), vomiting (16% to 40%), diarrhea (9% to 37%), constipation (29%), anorexia (23%), stomatitis (15%), abdominal pain (13%), decreased appetite (13%), dyspepsia (11%)

Hematologic & oncologic: Lymphocytopenia (68% to 99%; grades 3/4: 47% to 94%), bone marrow depression (grades 3/4: 98%; nadir: in week 3), leukopenia (61% to 94%; grades 3/4: 28% to 56%), decreased hemoglobin (88% to 89%; grades 3/4: 11% to 13%), decreased neutrophils (75% to 86%; grades 3/4: 43% to 60%), thrombocytopenia (77% to 86%; grades 3/4: 11% to 25%)

Hepatic: Increased serum bilirubin (34%)

Neuromuscular & skeletal: Back pain (14%), weakness (8% to 11%)

Respiratory: Cough (4% to 22%), dyspnea (16%)

Miscellaneous: Fever (24% to 34%)

• 1-10%:

Cardiovascular: Tachycardia (7%), chest pain (6%), hypotension (6%), exacerbation of hypertension (3%)

Central nervous system: Anxiety (8%), depression (6%), pain (6%)

Dermatologic: Pruritus (5% to 6%), hyperhidrosis (5%), night sweats (5%), xeroderma (5%)

Endocrine & metabolic: Hypokalemia (9%), hyperuricemia (7%), hyperglycemia (grades 3/4: 3%), hypocalcemia (grades 3/4: 2%), hyponatremia (grades 3/4: 2%)

Gastrointestinal: Gastroesophageal reflux disease (10%), xerostomia (9%), dysgeusia (7%), oral candidiasis (6%), abdominal distention (5%), upper abdominal pain (5%)

Genitourinary: Urinary tract infection (10%)

Hematologic & oncologic: Febrile neutropenia (grades 3/4: 6%)

Hepatic: Increased serum ALT (grades 3/4: 3%), increased serum AST (grades 3/4: 1%)

Hypersensitivity: Hypersensitivity (5%)

Infection: Herpes zoster (10%), infection (6%), herpes simplex infection (3%)

Local: Infusion site pain (6%), catheter pain (5%)

Neuromuscular & skeletal: Arthralgia (6%), limb pain (5%), ostealgia (5%)

Renal: Increased serum creatinine (grades 3/4: 2%)

Respiratory: Upper respiratory tract infection (10%), sinusitis (9%), pharyngolaryngeal pain (8%), pneumonia (8%), nasopharyngitis (6% to 7%), nasal congestion (5%), wheezing (5%)

• Frequency not defined:

Central nervous system: Drowsiness, malaise

Dermatologic: Dermatitis, skin necrosis

Gastrointestinal: Mucositis

Hematologic & oncologic: Hemolysis

• <1%:

 postmarketing, and/or case reports: Acute renal failure, anaphylactoid reaction, anaphylaxis, atrial fibrillation, bronchogenic carcinoma, bullous rash, cardiac failure, dermatological reaction (toxic), DRESS syndrome, erythema, extravasation injury, hepatitis, hepatotoxicity, injection site reaction (including irritation, pain, phlebitis, pruritus, swelling), myelodysplastic syndrome, myeloid leukemia (acute), myocardial infarction, neutropenic sepsis, palpitations, pancytopenia, pneumonia ( Pneumocystis jirovecii), pneumonitis, pulmonary alveolar hemorrhage (with grade 3 thrombocytopenia), pulmonary fibrosis, reactivation of disease (including, but not limited to hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, herpes zoster), sepsis, septic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, tumor lysis syndrome

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. Please report any adverse drug reactions via contacting Cedal Nano.⁽¹⁾

No in-vivo interaction studies have been performed.

When Ribocedal^® is combined with myelosuppressive agents, the effect of Ribocedal^® 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 Ribocedal^®.

Combination of Ribocedal^® 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.

Ribocedal^® metabolism involves cytochrome P450 (CYP) 1A2 isoenzyme. 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.

• Pregnancy

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

• Breast feeding

It is not known whether bendamustine passes into the breast milk, therefore, Ribocedal^® is contraindicated during breastfeeding.

Breastfeeding must be discontinued during treatment with Ribocedal^®.

• Fertility

Women of childbearing potential must use effective methods of contraception both before and during Ribocedal^® therapy.

Men being treated with Ribocedal^®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 Ribocedal^®.

– Keep the medicine in the box until it is consumed.

– store the medicine at temperatures below 30° C and protect from moisture.

– Keep the medicine out of the reach of children and pets.

-For storage conditions after reconstitution or dilution of the medicinal product, see section below:

– The final admixture is stable for 24 hours stored under refrigerated conditions at 2°C to 8°C (36°F to 46°F) or for 3 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light. Administration of reconstituted and diluted Bendamustine hydrochloride for Injection must be completed within this period