RECONSTITUTION, DOSING AND ADMINISTRATION

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2 CORRECT RECONSTITUTION FOR SC AND IV ADMINISTRATION VELCADE (bortezomib) 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration. Subcutaneous or Intravenous use only. Do not give by other routes. Intrathecal administration has resulted in death. Avoiding the potential risk of administration errors In order to avoid dosing errors, caution is required when preparing VELCADE as the volume required for reconstitution for the SC route is lower (1.4 ml) than that used for IV use (3.5 ml) giving a higher concentration of diluted drug (details are shown in tables 1 and 2). As the drug concentration after reconstitution differs between the SC and IV preparations, special care is required when calculating the volume of reconstituted drug, which will be delivered to the patient according to the prescribed dose. Please see pages 8-10 for examples of dosing for the different routes. VELCADE must be reconstituted by a Health Care Professional. Each vial of VELCADE must be carefully reconstituted by using a syringe of the appropriate size, without removing the vial stopper. Aseptic technique must be strictly observed throughout the handling of VELCADE since no preservative is present.

3 SUBCUTANEOUS ROUTE OF ADMINISTRATION Preparation of the 3.5 mg vial Each 3.5 mg vial of VELCADE must be reconstituted with 1.4 ml sterile sodium chloride 9 mg/ml (0.9 %) solution for injection dissolution of the lyophilised powder is completed in less than 2 minutes. Reconstitute the powder with 1.4 ml sodium chloride: inject the sodium chloride solution into the vial containing the lyophilised VELCADE. Table 1: Reconstitution of 3.5 mg VELCADE solution for SC injection Route of Reconstitution Final administration Pack size volume concentration Subcutaneous use only 3.5 mg 1.4 ml 2.5 mg/ml Reconstitution volume is less than that used for IV giving a more concentrated drug solution for injection The reconstituted solution should be clear and colourless. The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded. The final concentration is 2.5 mg/ml. PLEASE NOTE: The final drug concentration, when reconstituted for SC administration (2.5 mg/ml), is 2.5 times higher than that for the IV route (1 mg/ml) and therefore the volume required is lower when the SC route of administration is used. Once dissolved, withdraw the appropriate amount of the reconstituted drug solution: according to calculated dose based upon the patient s Body Surface Area (BSA). To avoid administration errors, syringes for SC and IV use should be labelled differently.

4 INTRAVENOUS ROUTE OF ADMINISTRATION Preparation of the 3.5 mg vial Each 3.5 mg vial of VELCADE must be reconstituted with 3.5 ml sterile sodium chloride 9 mg/ml (0.9%) solution for injection Dissolution of the lyophilised powder is completed in less than 2 minutes. Reconstitute the powder with 3.5 ml sodium chloride: inject the sodium chloride solution into the vial containing the lyophilised VELCADE. The reconstituted solution should be clear and colourless. The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded. The final concentration is 1.0 mg/ml. Table 2: Reconstitution of 3.5 mg VELCADE solution for IV injection Route of Reconstitution Final administration Pack size volume concentration Intravenous use 3.5 mg 3.5 ml 1.0 mg/ml Reconstitution volume is more than that used for SC giving a less concentrated drug solution for injection Once dissolved, withdraw the appropriate amount of the reconstituted drug solution: according to calculated dose based upon the patient s Body Surface Area (BSA). To avoid administration errors, syringes for SC and IV use should be labelled differently.

5 FOR SC & IV ADMINISTRATION Calculate the BSA using the slide rule. Additional examples are provided with the dosing slide rule. BSA: 1.7 m², Dose: 1.3 mg/m² BSA: 1.95 m², Dose: 1.3 mg/m² Intravenous Sample patient (1.7 m²) Subcutaneous Sample patient (1.7 m²) Intravenous Sample patient (1.95 m²) *Total volume rounded Subcutaneous Sample patient (1.95 m²) Diluent volume: 3.5 ml saline Diluent volume: 1.4 ml saline Diluent volume: 3.5 ml saline Diluent volume: 1.4 ml saline 1 mg/ml 2.5 mg/ml 1 mg/ml 2.5 mg/ml Dose: 1.3 mg/m² Dose: 1.3 mg/m² Dose: 1.3 mg/m² Dose: 1.3 mg/m² Total dose for patient: 2.21 mg Total dose for patient: 2.21 mg Total dose for patient*: 2.54 mg Total dose for patient*: 2.54 mg 2.2 ml 0.9 ml 2.5 ml 1 ml Injected IV (3-5 seconds push) Injected SC Injected IV (3-5 seconds push) Injected SC *Total volume rounded *Total volume rounded NOTE: If the calculated IV volume is used with the SC concentration, the patient will be overdosed. If the calculated SC volume is used with the IV concentration the patient will be underdosed. NOTE: If the calculated IV volume is used with the SC concentration, the patient will be overdosed. If the calculated SC volume is used with the IV concentration the patient will be underdosed.

6 BSA: 1.6 m², Dose: 1.0 mg/m² Intravenous Sample patient (1.6 m²) Diluent volume: 3.5 ml saline 1 mg/ml Dose: 1.0 mg/m² Total dose for patient: 1.6 mg 1.6 ml Injected IV (3-5 seconds push) *Total volume rounded Subcutaneous Sample patient (1.6 m²) Diluent volume: 1.4 ml saline 2.5 mg/ml Dose: 1.0 mg/m² Total dose for patient: 1.6 mg 0.64 ml Injected SC NOTE: If the calculated IV volume is used with the SC concentration, the patient will be overdosed. If the calculated SC volume is used with the IV concentration the patient will be underdosed. GENERAL INFORMATION General Precautions VELCADE is a cytotoxic agent. Therefore, caution should be applied when handling and preparing VELCADE. The use of gloves and other protective clothing to prevent skin contact is recommended. Please report any adverse event experienced with the administration of VELCADE immediately. Subcutaneous or Intravenous use only. Do not give by other routes. Intrathecal administration has resulted in death. Shelf life 3 Years. Reconstituted solution VELCADE is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. The reconstituted product is preservative free and should be used immediately after preparation. However, the chemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hours at 25 C stored in the original vial and / or syringe, with a total storage time for the reconstituted medicinal product not exceeding 8 hours prior to administration. It is not necessary to protect the reconstituted medicinal product from light.

7 CORRECT ADMINISTRATION FOR SC & IV VELCADE How to administer VELCADE SC? Confirm the dose in the syringe prior to use (check that the syringe is marked as SC administration). Inject the solution subcutaneously, at a angle. The reconstituted solution should be administered subcutaneously in the thighs or abdomen and injection sites should be rotated for successive injections. How to administer VELCADE IV? Confirm the dose in the syringe prior to use (check that the syringe is marked for IV administration). Inject the solution as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter into a vein. The use of IV hydration and an antiemetic medication as concomitant therapy prior to administration of IV VELCADE is recommended. Remind the patient to take the antiviral prophylaxis. Flush the peripheral or intravenous catheter with sterile 9 mg/ml (0.9 %) sodium chloride solution. Injections at the same site should be avoided Figure1. Injection site rotation Please report any adverse event experienced with the administration of VELCADE immediately. Alternate between - right and left abdomen (upper or lower quadrant) right and left thigh (proximal and distal sites) Remind the patient to take the antiviral prophylaxis. R L 5 4

8 VELCADE 3.5 mg POWDER FOR SOLUTION FOR INJECTION PRESCRIBING INFORMATION ACTIVE INGREDIENT: Bortezomib Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATIONS: Adults only. Monotherapy or with pegylated liposomal doxorubicin or dexamethasone: progressive multiple myeloma in patients who have had at least 1 prior therapy and already undergone/are not suitable for haematopoietic stem cell transplant. With melphalan & prednisone: for previously untreated multiple myeloma in patients not eligible for high-dose chemotherapy with haematopoietic stem cell transplant. With dexamethasone, or with dexamethasone and thalidomide: for induction treatment of previously untreated multiple myeloma in patients eligible for high-dose chemotherapy with haematopoietic stem cell transplant. With rituximab, cyclophosphamide, doxorubicin and prednisone: for previously untreated mantle cell lymphoma (MCL) in patients unsuitable for haematopoietic stem cell transplantation. DOSAGE & ADMINISTRATION: Adults and Elderly: Administer as 3-5 second IV bolus or SC in thighs/abdomen. At least 72 hours between consecutive doses. Recommended dose 1.3mg/m 2 body surface area. Posology modifications required for VELCADE-related toxicity, refer to SmPC. Treatment of progressive multiple myeloma (after at least 1 prior therapy) VELCADE treatment cycle: twice weekly for 2 weeks in 21-days treatment cycle. Two cycles of VELCADE recommended following confirmation of complete response. Responding patients without complete remission should receive total of 8 cycles. Monotherapy: as above. Combination with pegylated liposomal doxorubicin: 30mg/m² pegylated liposomal doxorubicin (1h IV infusion) on day 4 of VELCADE treatment cycle. Combination with dexamethasone: 20mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of VELCADE treatment cycle. Previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplant Combination with oral melphalan (9mg/m 2 ) and prednisone (60mg/m 2 ): 9 6-weeks treatment cycles. Previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplant (induction therapy) Combination with oral dexamethasone (40mg): 4 21-days treatment cycles. Combination with oral dexamethasone (40mg) and thalidomide (50mg): 4 28-days treatment cycles. At least partial responders: 2 additional cycles. For other medicinal products, see appropriate SmPCs. Previously untreated mantle cell lymphoma not suitable for haematopoietic stem cell transplantation Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP): days treatment cycles. (For other medicinal products, see appropriate SmPCs.) Children: no recommendation on posology can be made; refer to SmPC for current available data. Hepatic Impairment: mild - no dose adjustment; moderate or severe - start on reduced dose of 0.7mg/m 2 per injection for first cycle, then possible increase to 1.0mg/m 2 or reduction to 0.5mg/m 2 based on tolerability. Renal Impairment: See precautions. CONTRAINDICATIONS: Hypersensitivity to active substance, boron or any excipients. Acute diffuse infiltrative pulmonary and pericardial disease. SPECIAL WARNINGS & PRECAUTIONS: Do not administer intrathecally. Monitor complete blood counts; consider platelet transfusion. GI toxicity very common; monitor closely. In MCL, transient neutropenia reported between cycles; monitor for signs/symptoms of infection, treat promptly; consider prophylactic granulocyte colony stimulating factors if delayed cycles. Herpes zoster virus reactivation: anti-viral prophylaxis recommended. Screen for Hepatitis B Virus reactivation/infection when rituximab combination; consider antiviral prophylaxis (see SmPC for rituximab). Very rarely John Cunningham virus infection resulting in Progressive Multifocal Leukoencephalopathy (PML) and death; monitor regularly for PML symptoms, discontinue if diagnosed. Peripheral neuropathy common; requires careful monitoring, neurological evaluation and possible dose/schedule modification, or change to SC route. Special care if risk factors for seizures. Caution when history of syncope with medicinal products linked with hypotension, or dehydration due to recurrent diarrhoea/vomiting. Discontinue treatment if Posterior Reversible Encephalopathy Syndrome (PRES) occurs. Development/exacerbation of congestive heart failure/qt prolongation; monitor closely if cardiac risk factors. Renal impairment common; monitor closely. Rarely acute diffuse infiltrative pulmonary disease of unknown aetiology e.g. pneumonitis, interstitial pneumonia, lung infiltration and acute respiratory distress syndrome (ARDS); baseline chest radiograph recommended. If new/worsening pulmonary symptoms perform prompt diagnostic evaluation and treat appropriately; consider benefit/risk ratio before continuing. Immunocomplex-mediated reactions e.g. serum sickness, polyarthritis with rash, proliferative glomerulonephritis: discontinue if severe. Bortezomib exposure increased in moderate/severe hepatic impairment; reduce doses, closely monitor. Patients with high pre-treatment tumour burden at risk of tumour lysis syndrome; monitor closely. Concomitant CYP3A4-inhibitors: monitor closely. Caution with CYP3A4 or CYP2C19 substrates. SIDE EFFECTS: Very common: thrombocytopenia, neutropenia, anaemia, decreased appetite, neuropathies, peripheral sensory neuropathy, dysaesthesia, neuralgia, nausea, vomiting, diarrhoea, constipation, fatigue, pyrexia, asthenia. Multiple Myeloma: musculoskeletal pain. MCL: pneumonia, febrile neutropenia, leukopenia, lymphopenia, stomatitis, hair disorder. Common: herpes zoster (inc disseminated & ophthalmic), herpes simplex, fungal infection, hypokalaemia, hyponatraemia, blood glucose abnormal, sleep disorders & disturbances, motor neuropathy, loss of consciousness (inc syncope), dizziness, dysgeusia, vision abnormal, hypotension, orthostatic hypotension, hypertension, dyspnoea, upper/lower respiratory tract infection, cough, gastrointestinal haemorrhage (inc mucosal), dyspepsia, abdominal distension, oropharyngeal pain, abdominal pain (inc gastrointestinal and splenic pain), oral disorder, rash, pruritus, muscle spasms, pain in extremity, oedema (inc peripheral), chills, malaise, weight decreased. Multiple Myeloma: pneumonia, leukopenia, lymphopenia, dehydration, hypocalcaemia, enzyme abnormality, mood disorders & disturbances, anxiety disorder, lethargy, headache, eye swelling, conjunctivitis, vertigo, epistaxis, stomatitis, flatulence, hepatic enzyme abnormality, erythema, dry skin, muscular weakness, renal impairment, pain. MCL: sepsis (inc septic shock), Herpes virus infection, bacterial infections, hypersensitivity, diabetes mellitus, fluid retention, neuropathies, encephalopathy, peripheral sensorimotor neuropathy, autonomic neuropathy, dysacusis (inc tinnitus), cardiac fibrillation (inc atrial), arrhythmia, cardiac failure (inc left and right ventricular), myocardial ischaemia, ventricular dysfunction, hiccups, gastritis, oral ulceration, abdominal discomfort, dysphagia, gastrointestinal inflammation, hepatotoxicity (inc liver disorder), dermatitis, musculoskeletal pain, urinary tract infection, injection site reaction, hyperbilirubinaemia, protein analyses abnormal, weight increased. Other side effects include: tumour lysis syndrome, pulmonary hypertension, pancytopenia, anaphylactic shock/reaction, hearing impaired (up to and inc deafness), cardiovascular disorder (inc cardiogenic shock), pulmonary embolism, acute respiratory distress syndrome, colitis (inc clostridium difficile), hepatic failure. Multiple Myel oma: cardiac failure, Posterior Reversible Encephalopathy Syndrome, acute diffuse infiltrative pulmonary disorders, autonomic neuropathy, sepsis, herpes virus infection, meningitis, meningoencephalitis herpetic, Epstein-Barr virus infection, neoplasm malignant, leukaemia plasmacytic, mycosis fungoides, neoplasm benign, lymphadenopathy, febrile neutropenia, thrombocytopenic purpura, hypersensitivity, type III immune complex mediated reaction, Cushing s syndrome, mental disorder, suicidal ideation, psychotic disorder, haemorrhage intracranial, peripheral sensory motor neuropathy, encephalopathy, neurotoxicity, cerebral haemorrhage, seizure disorders, paralysis, coma, eye haemorrhage, optic neuropathy, different degrees of visual impairment, cardiac tamponade, cardiopulmonary arrest, cardiac fibrillation, arrhythmia, tachycardia, angina pectoris, pericarditis, cardiomyopathy, ventricular dysfunction, atrial flutter, myocardial infarction, atrioventricular block, torsade de pointes, angina unstable, cardiac valve disorders, sinus arrest, cerebrovascular accident, deep vein thrombosis, thrombophlebitis, phlebitis, vasculitis, peripheral embolism, pulmonary alveolar haemorrhage, bronchospasm, wheezing, respiratory failure, apnoea, haemoptysis, respiratory alkalosis, throat tightness, pancreatitis, haematemesis, gastro-intestinal obstruction, enteritis, megacolon, peritonitis, gastrointestinal ulceration & perforation, hepatotoxicity, hepatitis, cholestatis, hepatic haemorrhage, acute febrile neutrophilic dermatosis, toxic skin eruption, toxic epidermal necrolysis, Stevens- Johnson syndrome, purpura, erythema multiforme, myopathies, rhabdomyolysis, renal failure, urinary retention, oliguria, death, multi-organ failure, ECG abnormality. MCL: hepatitis B infection, bronchopneumonia, autonomic nervous system imbalance, vertigo, pneumonitis, pulmonary oedema (inc acute). Refer to SmPC for other side effects. PREGNANCY: No clinical data available for bortezomib. Thalidomide contraindicated during pregnancy and in women of childbearing potential unless all conditions of thalidomide pregnancy prevention programme met. Male and female patients of childbearing potential must use effective contraceptive measures during treatment and for 3 months following. LACTATION: Not recommended. INTERACTIONS: Closely monitor when bortezomib is combined with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir). Concomitant use of bortezomib with strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John s Wort) not recommended. Hypo/hyperglycaemia reported in diabetic patients receiving oral hypoglycaemics. LEGAL CATEGORY: Prescription Only Medicine PRESENTATION, PACK SIZE, MARKETING AUTHORISATION NUMBER: MARKETING AUTHORISATION HOLDER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. Janssen- Cilag Limited 2016 Prescribing information last revised: January 2016 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: , Fax: , Website: medsafety@hpra.ie Adverse events should also be reported to Janssen-Cilag Limited on Please refer to Summary of Product Characteristics (SmPC) for further instructions IRE/VEL/2012/0071(2) Date of preparation: May 2017

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