This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States BMC Medicine 2013, 11:18 Aurore Thibaut () Julia C Nantes ()
Roche-plus.co.nzThe GAZYVA® dosing
and administration guide
A guide for health care professionals administering GAZYVA
to patients with chronic lymphocytic leukaemia (CLL).
DAYS 1 AND 2
CYCLE 1, DAYS 8 AND 15, CYCLES 2-6, DAY 1
Patients with a
without any IRR with Grades
Grade 3 (severe)
1–2 (mild to
IRR with the
previous infusion with the previous OR with a count >25 x 109/l COMPLETE 60 MINUTES PRIOR TO INFUSION
(100 mg prednisone/ prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone)a
30 MINUTES PRIOR TO INFUSION
(eg, 50 mg diphenhydramine)30 MINUTES PRIOR TO INFUSION Oral analgesic/antipyretic (eg, 1000 mg acetaminophen/ a. Hydrocortisone is not recommended as it has not been effective in reducing the role of infusion reactions Hypotension may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour For patients with high tumour burden and/or high circulating absolute lymphocyte counts (>25 x 109/L), premedicate with antihyperuricemics (eg, allopurinol) beginning 12-24 hours prior to start of therapy and ensure adequate hydration for prophylaxis of tumour lysis syndrome Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered1 Pre-medicate before each infusion Administer as an intravenous infusion through a dedicated line. Do not administer as an intravenous Do not mix GAZYVA with other drugs No incompatibilities between GAZYVA and polyvinyl chloride (PVC) or polyolefin bags and administration sets have been observed Monitor blood counts at regular intervals GAZYVA should be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur DOSING AND ADMINISTRATION
GAZYVA is administered in 6 treatment cycles, each 28 days in duration1
†After infusion of GAZYVA.
For Days 1 and 2 of Cycle 1, the 1000 mg GAZYVA vial will be split between 100 mg and 900 mg, chlorambucil respectively. For Cycles 1 to 6, chlorambucil (Clb) is administered orally on Days 1 and 15 at 0.5 mg/kg.1 The first 1000 mg
CYCLE 1 (FIRST 1000 MG)
Bag 1 (100 mg)
Bag 2 (900 mg)
Start at 25 mg/h Start at 50 mg/h. Rate can be increased by 50 mg/h every 30 the infusion rate.
minutes to a maximum rate of 400 mg/h.
For the first infusion, prepare two bags (containing 100 mg and 900 mg of GAZYVA) to be administered If the patient completes Bag 1 (100 mg of GAZYVA) with no infusion-related symptoms, it is possible to continue on to Bag 2 (900 mg of GAZYVA) the next day Subsequent 1000 mg doses
CYCLE 1 (CONTINUED)
Cycle 1 (continued): days 8, 15 Cycles 2-6: day 1 Start at 100 mg/h. Rate can be increased by 100 mg/h every 30 minutes, to a maximum of 400 mg/h.
• Each cycle is 28 days in duration a Chlorambucil (Clb) is administered oral y at 0.5mg/kg after GAZYVA infusion.
b Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or a ≥ Grade 2 non - hermatologic toxicity.
PREPARATION AND STORAGE
Dosage form and strength1
1000 mg/40 ml (25 mg/ml) single-use vial Prepare the solution for infusion, using aseptic technique, as follows:1
1. Inspect visually for any particulate matter and discolouration prior to administration
2. GAZYVA does not contain antimicrobial preservatives. Therefore, care must be taken to ensure
that the solution for infusion is not microbiologically compromised during preparation 3. Withdraw the appropriate volume of GAZYVA solution from the vial VOLUME OF GAZYVA TO ADMINISTER FOR VARIOUS DOSES
Dose of GAZYVA
Volume of GAZYVA
to be administered
from the 40 ml vial
4. Dilute into a 250 ml 0.9% sodium chloride PVC or polyolefin infusion bag. Other diluents such as dextrose (5%) solution should not be used 5. Mix diluted solution by gentle inversion. Do not shake or freeze6. From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.
IMPORTANT SAFETY INFORMATION
GAZYVA can cause severe and life-threatening infusion reactions. Symptoms may include hypotension, tachycardia, dyspnoea, and respiratory symptoms. Other common symptoms include nausea, vomiting, diarrhoea, hypertension, flushing, headache, pyrexia, and chills Premedicate patients before each infusion. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication Tumour Lysis Syndrome (TLS)1
TLS can occur within 12-24 hours after the first infusion. Patients with high tumour burden and/ or high circulating lymphocyte count (>25 x 109/L) are at greater risk for TLS and should receive appropriate tumour lysis prophylaxis with antihyperuricemics (e.g. allopurinol) and hydration beginning12-24 hours prior to the infusion of GAZYVA Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection Patients with severe neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days) Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered GAZYVA can cause acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. In patients with severe thrombocytopenia, monitor platelet counts frequently until resolution Immunisation with live virus vaccines is not recommended during treatment and until B-cell recovery Additional Important Safety Information1
The most common adverse reactions (incidence ≥10%) were: infusion reactions, neutropenia, thrombocytopenia, anaemia, pyrexia, cough, and musculoskeletal disorders MANAGEMENT OF INFUSION-RELATED REACTIONS
The most common symptoms of infusion-related reactions for GAZYVA
and chlorambucil are chills, nausea, pyrexia, hypotension and vomiting1
If a patient experiences an infusion-related reaction during infusion, adjust the infusion as outlined below:1 Grade 4 (life-threatening)
Stop infusion and permanently discontinue therapy
Grade 3 (severe)
Temporarily interrupt infusion and treat symptoms
• Upon resolution of symptoms, restart infusion at no more than half
the previous rate (the rate being used at the time that the infusion reaction occurred) • If patient does not experience any infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dosea • Stop infusion and permanently discontinue therapy if patients experience a second occurrence of a Grade 3 infusion reaction Grade 2 (moderate)
Reduce infusion rate and treat symptoms
• Upon resolution of symptoms, continue infusion
Grade 1 (mild)
• If patient does not experience any infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dosea aThe Day 1 infusion rate may be increased back up to 25 mg/h after 1 hour, but not increased further. Dosing modification
No dose modification of GAZYVA is recommended1 Infusion should be interrupted or slowed if patients experience infusion reactions1 If a planned dose of GAZYVA is missed, it should be administered as soon as possible and the next cycle should begin 28 days later; do not wait until the next planned dose1 Reference: 1. GAZYVA (obinutuzumab) Data Sheet, 14 January 2015.
GAZYVA® (obinutuzumab) ABRIDGED PRESCRIBING INFORMATION. GAZYVA concentrate solution for IV infusion (1000mg/40mL; 25 mg/mL, packs of 1) is a Prescription Medicine indicated in
combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukaemia (CLL). Dosage & Administration: Please refer to the GAZYVA Data Sheet for information.
Contraindications: Patients with a known hypersensitivity (IgE mediated) to obinutuzumab or to any of the excipients. Precautions: Severe, life-threatening infusion related reactions (IRRs) have been
reported. Follow premedication instructions and modify infusion rate as advised under Dosage & Administration (see Data Sheet). Stop infusion and permanently discontinue for Grade 4 IRRs, second occurrence of Grade 3 IRR or acute life-threatening respiratory symptoms. Carefully monitor patients with pre-existing cardiac or pulmonary conditions. Consider withholding antihypertensive medication for 12 hours prior to, during, and the first hour after infusion. Hypersensitivity including anaphylaxis; stop and discontinue permanently in these patients. Patients at high risk of tumour lysis syndrome (TLS) should receive
prophylaxis with uricostatics and hydration starting 12-24 hrs prior to infusion. For TLS treatment, correct electrolyte abnormalities, monitor renal function and fluid balance; administer supportive care, including dialysis as indicated. All at risk patients should be carefully monitored during initial treatment. Severe/life-threatening neutropenia including febrile neutropenia, late onset, and prolonged neutropenia have been
reported. Closely monitor patients until resolution. Treat concomitant infection; consider G-CSF therapy. Severe/life-threatening thrombocytopenia including acute thrombocytopenia, and fatal haemorrhagic
events have been reported during Cycle 1 infusion. Closely monitor patients; perform regular laboratory tests until the event resolves. Transfusion of blood products is at the discretion of the treating physician. Worsening of pre-existing cardiac conditions has been observed in patients with underlying cardiac disease. These events may occur as part of an IRR and can be fatal. Closely monitor patients with a history
of cardiac disease. Hydrate with caution. Do not administer to patients with active infections and exercise caution in those with a history of recurring or chronic infections. Serious bacterial, fungal, and new
or reactivated viral infections can occur during and following the completion of therapy. Potential HBV reactivation; screen all patients prior to treatment. Do not treat patients with active disease and refer
patients with positive serology to a specialist before commencing treatment. Progressive multifocal leucoencephalopathy (PML) has been reported in patients treated with anti-CD20 antibodies including
GAZYVA. Consider PML in any patient presenting with new-onset neurologic manifestations. Withhold treatment during investigation and permanently discontinue if PML is confirmed. Immunisation with live
virus vaccines is not recommended until B-cell recovery. In the pivotal trial patients with moderate renal impairment (CrCl <50 mL/min) experienced more SAEs and AEs leading to death than those with CrCl
≥50 mL/min. Safety and efficacy in patients with hepatic impairment and in paediatric patients (<18 years old) have not been established. Elderly patients (≥75 years old) experienced more SAEs and AEs
leading to death than those <75 years old in the pivotal trial. Patients experiencing infusion-related symptoms should not drive or operate machines until symptoms abate. No formal drug-drug interaction
studies have been performed. Pregnancy: Category C. Avoid treatment during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. Use effective contraception
during treatment and for 18 months following treatment. Discontinue breast-feeding during therapy and for 18 months after the last dose. Newborns to mothers who have been exposed to GAZYVA during pregnancy should not receive live vaccines until B-cell levels are within normal ranges. Adverse Effects: (See Data Sheet for complete list). IRRs characterised by nausea, chills, hypotension, pyrexia, vomiting,
dyspnoea, flushing, hypertension, headache, tachycardia, and diarrhoea; respiratory and cardiac symptoms including bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and atrial fibrillation. Neutropenia, thrombocytopenia, leucopenia, anaemia, UTI, oral herpes, rhinitis, pharyngitis, nasopharyngitis, cough, TLS, hyperuricaemia, arthralgia, back pain, musculoskeletal chest pain, decreased WBC count, decreased neutrophil count, weight increase, squamous cell carcinoma of skin, constipation, alopecia. Transient elevation in liver enzymes shortly after the first infusion.
GAZYVA is an unfunded medicine.
Before prescribing, please review the GAZYVA Data Sheet available at www.medsafe.govt.nz. API based on Data Sheet 25.03.2015.
Roche Products (New Zealand) Limited, Auckland. Ph 0800 656 464. www.roche.co.nz All trademarks mentioned herein are protected by law.
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