SUBCUTANEOUS Bortezomib + Thalidomide +Dexamethasone Available for Routine Use in

Transcription

1 SUBCUTANEOUS Bortezomib + Thalidomide +Dexamethasone Available for Routine Use in Burton in-patient Derby in-patient Burton day-case Derby day-case Burton community Derby community Burton out-patient Derby out-patient Indication Induction treatment of adults with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation. Treatment Intent Disease modification Anti-Emetics Pre-chemotherapy Nil Frequency & Duration Post-chemotherapy Metoclopramide prn Every 28 days, up to 6 cycles may be given to patients who achieve at least a partial response after 4 cycles Day 1 Bortezomib 1.3mg/m 2 Subcutaneous bolus over 3-5 seconds Thalidomide mg Oral ONCE daily (at night) for 28 days (See notes below re.: dose escalation) Dexamethasone 40mg Oral ONCE daily for 4 days Metoclopramide 10mg Oral FOUR times daily as required Aspirin 75mg Oral ONCE daily for 28 days (See notes below) or Enoxaparin 40mg Subcutaneous injection ONCE daily for 28 days (See notes below) Omeprazole 20mg Oral ONCE daily for 28 days Co-trimoxazole 480mg Oral ONCE daily for 28 days Fluconazole 50mg Oral ONCE daily for 28 days Aciclovir 400mg Oral TWICE daily for 28 days Allopurinol 300mg Oral ONCE daily for 28 days (Cycle 1. Reduce dose in renal impairment) Day 4 Bortezomib 1.3mg/m 2 Subcutaneous bolus over 3-5 seconds Day 8 Bortezomib 1.3mg/m 2 Subcutaneous bolus over 3-5 seconds Dexamethasone 40mg Oral ONCE daily for 4 days Day 11 Bortezomib 1.3mg/m 2 Subcutaneous bolus over 3-5 seconds REVIEWED BY: C.WARD AUTHORISED BY: Dr D Allotey PAGE 1 of 6

2 Notes: Treatment must commence on a Monday or Tuesday in view of the dosing schedule Thalidomide is administered orally at 50 mg daily on of cycle 1 and if tolerated the dose is increased to 100 mg on cycle 2, and may be further increased to 200 mg daily from cycle 3. Pregnancy testing Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test (minimal sensitivity 50mlU/min) performed by a healthcare professional Within 24 hours before starting thalidomide Every 4 weeks in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles while on thalidomide 4 weeks after the last dose of thalidomide Prescribing of thalidomide Ensure that patients are given a thalidomide information sheet Patients should be prescribed no more than 28 days supply of thalidomide at any one time Prescribing clinicians, consenting patients and pharmacies must register with the Pharmion Risk Management Centre: In WCBP a pregnancy test should have been performed in the 24 hours before thalidomide is issued and a negative result confirmed. To further reduce the risk for existing pregnancy whilst starting thalidomide, it is recommended that, where possible, the drug is started within 3 days following the onset of menstrual bleeding In WCBP a negative pregnancy test should have been performed in the 24 hours before all repeat thalidomide supplies are issued Dose modification (Thalidomide) a. Thromboembolism The occurrence of a thromboembolic event is an indication for anticoagulation following standard treatment Thalidomide should be stopped but can be re-introduced, initially at 50mg daily with escalation at subsequent cycles to 100mg, assuming good anticoagulant control and no other untoward side effects b. Pregnancy or suspected pregnancy Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease status) of a patient or a male patient s partner occurring while the patient is on thalidomide, or within 4 weeks after the last dose, are indications to discontinue thalidomide immediately REVIEWED BY: C.WARD AUTHORISED BY: Dr D Allotey PAGE 2 of 6

3 and to ask the patient to return any unused portion of the medication to the investigator Female patients should be referred to an obstetrician/gynaecologist experienced in reproductive toxicity for further evaluation and counselling c. Adjustments for neutropenia and/or thrombocytopenia It is presumed that evidence of myelosuppression prior to initial treatment in previously untreated patients will be a reflection of bone marrow infiltration. Unless there is evidence suggesting another cause, patients should be given at least the first cycle with unmodified doses If persistent cytopenias are considered to be due to marrow infiltration, dose modification is not necessarily indicated If the cytopenias are treatment-related, omission of cyclophosphamide for 1-3 weeks or reduction of the dose (e.g. to 400mg or 300mg) would be reasonable However, the use of G-CSF for a few days per cycle to maintain adequate neutrophil counts is also appropriate. For subcutaneous administration the Bortezomib injection concentration must be 2.5mg/ml (See separate protocol for intravenous administration). As the drug concentration after reconstitution differs between the subcutaneous and intravenous preparations, special care is required when calculating the volume of reconstituted drug required to deliver the prescribed dose in order to avoid potential dosing errors Preferred anatomical areas of SC administration are the thighs (proximal and distal sites) or abdomen (upper and lower quadrants) and injection sites should be rotated within a treatment cycle to avoid injections at the same site. i.e. REVIEWED BY: C.WARD AUTHORISED BY: Dr D Allotey PAGE 3 of 6

4 Platelet counts should be monitored prior to the 1st dose of Bortezomib. Routine midcycle check of platelet counts is not necessary. Checks should only be undertaken if advised by the treating clinician (e.g. if pre-treatment platelets are less than 50 x 10 9 /L due to underlying myeloma). Bortezomib should be omitted (not delayed) when the platelet count is <25 x 10 9 /L and re-initiated at a reduced dose after resolution (see below). If thrombocytopaenia is due to disease, then administer a platelet transfusion and proceed with treatment. Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding Treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy (see below). Once the symptoms of the toxicity have resolved, bortezomib may be re-initiated at a 25% reduced dose (1.3 mg/m 2 reduced to 1.0 mg/m 2 ; 1.0 mg/m 2 reduced to 0.7 mg/m 2 ). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of treatment must be considered unless the benefit of treatment clearly outweighs the risk. Patients who experience bortezomib related neuropathic pain and/or peripheral neuropathy are to be managed as presented in the table below. Patients with pre-existing severe neuropathy may be treated with bortezomib only after careful risk/benefit assessment. Recommended dose modifications for bortezomib related neuropathic pain and/or peripheral sensory neuropathy. Severity of Peripheral Neuropathy Signs and Symptoms Grade 1 (paresthesia and/or loss of reflexes) without pain or loss of function Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living) Grade 2 with pain or Grade 3 (interfering with activities of daily living) Grade 4 (Permanent sensory loss that interferes with function) Modification of Dose and Regimen Reduce Bortezomib to 1.0 mg/m 2 Reduce bortezomib to 0.7 mg/m 2 Withhold bortezomib therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of bortezomib at 0.7 mg/m 2 and change treatment schedule to once per week Discontinue bortezomib Bortezomib Dose Modification in Renal Impairment The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (Creatinine Clearance (CrCL) > 20 ml/min/1.73 m 2 ); REVIEWED BY: C.WARD AUTHORISED BY: Dr D Allotey PAGE 4 of 6

5 therefore, dose adjustments are not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CrCL < 20 ml/min/1.73 m 2 ). Since dialysis may reduce bortezomib concentrations, Bortezomib should be administered after the dialysis procedure Bortezomib Dose Modification in Hepatic Impairment Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m 2 during the first treatment cycle, and a subsequent dose escalation to 1.0 mg/m 2 or further dose reduction to 0.5 mg/m 2 may be considered based on patient tolerability. Grade of hepatic impairment* Mild Bilirubin Level SGOT (AST) Levels Modification of Starting Dose 1.0x ULN > ULN None Moderate > 1.0x 1.5x ULN Any None > 1.5x 3x ULN Any Reduce Bortezomib dose to 0.7 mg/m 2 in the first treatment cycle. Consider dose escalation to 1.0 mg/m 2 or further dose reduction to 0.5 mg/m 2 in subsequent cycles based on patient tolerability. Other side effects Thalidomide related toxicity may be encountered and includes constipation, neuropathy, fatigue, sedation, rash, tremor and oedema Grade 3-4 toxicity is an indication to stop thalidomide for the remainder of the current cycle and then re-introduce at 50mg daily with the next or subsequent cycle. Assuming tolerance at the lower dose level, escalation to 100mg daily may be considered, and possibly to 150mg or the full 200mg dose if the symptoms resolve and do not recur Occasionally patients will be unable to tolerate Dexamethasone at the protocol doses. Omission of one of the two 4-day pulses of Dexamethasone in a 3-week cycle would be an alternative approach Switching to another corticosteroid, e.g. methylprednisolone, although rarely appropriate would also be permissible. Supportive care Unless contra-indicated all patients should receive the following prophylactic agents for the duration of their chemotherapy Co-trimoxazole 480mg oral ONCE daily Aciclovir 400mg oral TWICE daily Fluconazole 50mg oral ONCE daily REVIEWED BY: C.WARD AUTHORISED BY: Dr D Allotey PAGE 5 of 6

6 Omeprazole 20mg ONCE daily Thromboprophylaxis 1. Patients treated with thalidomide have an increased risk of arterial thromboembolism, including myocardial infarction and cerebrovascular events, in addition to the established risk of venous thromboembolism 2. Action should be taken to minimise all modifiable risk factors for thromboembolic events (eg, smoking, hypertension, and hyperlipidaemia) 3. Healthcare professionals should consider venous and arterial thrombotic risk and administer antithrombotic prophylaxis for at least the first 5 months in patients commencing thalidomide e.g. aspirin 75mg once daily (unless contra-indicated). Clinicians may wish to consider low-dose enoxaparin (40mg once daily by subcutaneous injection) for those with previous history of TED) References 1. NICE technology appraisal guidance 311; Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation; Issued: April Janssen Summary of Product Characteristics last updated on the emc: 23/01/2014 (Accessed 28/4/14) REVIEWED BY: C.WARD AUTHORISED BY: Dr D Allotey PAGE 6 of 6