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CONFIDENTIAL 111
Pharmacy & Investigational Supply Management
Privileged and Confidential
CONFIDENTIAL
Investigational Product & Supply Management
• Review of brentuximab vedotin(ADCETRIS™)– Formulation & Packaging– Shipment & Receipt– Storage & Handling
• Preparation– Dose Calculation– Reconstitution– Administration
• Supply Management– Initial Drug Shipment– Re-supply– Accountability– Returns / Destruction
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CONFIDENTIAL 3
Brentuximab vedotin (ADCETRIS™)Formulation
• Cytotoxic agent to be handled with caution
• Single use vial containing 50mg (note: vials contain
55mg fill / 50mg usable brentuximab vedotin)
• Sterile, preservative-free, and white to off-white
lyophilized cake for reconstitution for IV administration
• After reconstitution with 10.5 mL
sterile Water for Injection, USP,
yields 11 mL of brentuximab vedotin
solution (5 mg/mL)
• Temperature sensitive (2-8ºC)
CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™)Packaging Design
• Vials packaged in 1x tamper-sealed carton
• Each vial and carton affixed with
single-panel label– Each vial and carton must be stored in together until
required for reconstitution– Identified with a Lot Number and Medication Number– Vials and cartons are not considered patient specific
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™)Shipment & Receipt
• Shipments originate from Almac Clinical Services (Durham, NC)
• ADCETRIS™ shipped refrigerated at 2-8C• Each shipment contains:
– TagAlert temperature monitoring device– TagAlert instructions– Almac packaging slip
• Shipments must be received within 24 hours• Shipments received out of temperature range must
be quarantined at 2-8C and not used until further instruction is received from ICON
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™)Shipment & Receipt (cont.)
• Upon receipt of the drug shipment, please take the following IMMEDIATE action: – Step 1. Remove the TagAlert monitor from the package and store
study drug in the appropriate temperature controlled environment. Please be aware this monitor does not need to be stopped
– Step 2: If the LCD is displaying the “OK” icon, no alarms have been triggered during the trip
– Step 3: If the LCD is displaying black squares over the “OK” and the numbers 1, 2, 3 and/or 4, then an alarm has been triggered. Note: If any of the numbers appear on the LCD, that alarm has triggered. The “OK” may still be visible through the black squares even if an alarm has been triggered
– Step 4: Indicate the status of the monitor at receipt of the shipment on the instruction sheet. If the shipment has alarmed, record the time stamps and identification numbers.
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™)Shipment & Receipt (cont.)
• Refer to Bracket – Millennium C25003 Site User Instruction Manual to receive shipment in IXRS– IXRS will not dispense drug unless this acknowledgement step
has been conducted– IXRS will ask for confirmation if:
• shipment included a temperature monitoring device• any study drug was damaged• shipment was received within temperature range
– ICON CRA or study management should be contacted if damage or a temperature excursion is detected during the receipt process
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CONFIDENTIAL 88
Brentuximab vedotin (ADCETRIS™)Storage and Handling
• Storage– ADCETRIS™ vials/cartons must be stored refrigerated at 2–8°C in
an appropriate locked room accessible only to the pharmacist, the investigator, or a duly designated person
– Refrigerator temperature logs must be maintained• Report storage temperature excursions immediately to CRA• Temperature excursions evaluated by Millennium on an individual basis
– Recommend protecting all vials and solutions from direct sunlight until the time of use
• Handling– ADCETRIS™ does not contain preservatives
• Opened vials and reconstituted solution must be used within 24 hours • Reconstituted solution must not be stored at room temperature
– Reconstituted solution and infusion bags must not be shaken
CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™) Dose Calculation
• Initial dose of brentuximab vedotin is based on the Day 1 weight
• Patients must be weighed at each dosing visit– The dose must be adjusted if the weight has increased or
decreased by at least 10% from Day 1– When there is a 10% weight change, continue to use the
new dose until the weight changes (+/-) by an additional 10%
• Dose calculation should be rounded to the nearest whole number of milligrams.
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™)Reconstitution
• Dose preparation steps:1. Remove the plastic flip-off caps from the necessary number of vials of
brentuximab vedotin
2. Reconstitute lyophilized brentuximab vedotin by adding 10.5 mL Sterile Water for Injection, USP to the vial, directing the stream at the side of the vial
3. GENTLY swirl the vial until the contents are completely dissolved. Slight “bubbling” of the solution upon reconstitution may be observed. Allow the reconstituted vial to settle for a minute to allow bubbles to dissipate. Do not shake or vigorously swirl.
4. The reconstituted product should be a colorless, clear to slightly opalescent solution with no visible particulates, with a total volume of 11 mL (5 mg/mL). The reconstituted solution should be visually inspected for any particulate matter and discoloration.
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™)Reconstitution (cont.)
• Dose preparation steps (continued):5. Withdraw the required volume of reconstituted brentuximab vedotin and
dilute in an infusion bag containing 0.9% Sodium Chloride Injection
• There are no known incompatibilities between study treatment and polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), polyolefin, or polyethylene (PE) bags
• The infusion volume needs to be set such that when the dose of brentuximab vedotin is diluted in the bag, the final drug concentration is between 0.4 and 1.8 mg/mL
6. Gently invert the infusion bag (as applicable); DO NOT SHAKE.
7. Diluted brentuximab vedotin for injection should be administered immediately (if not administered immediately, the in-use storage should not be longer than 24 hours under refrigeration at 2–8°C).
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™) Administration
• In the absence of infusion toxicities, the infusion rate for all patients must be calculated in order to achieve a 30 minute infusion period
Note: Compatibility of brentuximab vedotin has not been assessed with in-line filters
• ADCETRIS™ must:– NOT BE ADMINISTERED AS AN IV PUSH OR BOLUS. – Be administered through a dedicated IV line over 30 minutes– NOT be mixed with other medications
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CONFIDENTIAL
Brentuximab vedotin (ADCETRIS™) Administration (cont.)
• Infusion-related reactions may occur during the infusion– Patient must be observed for 60 minutes following the first
infusion, during which time a functioning IV line must remain to allow administration of IV medications if necessary.
– All supportive measures consistent with optimal patient care will be given throughout the study according to institution standards. Medications for infusion-related reactions, such as epinephrine, antihistamines, and corticosteroids, must be available for immediate use.
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CONFIDENTIAL
Supply ManagementInitial and Resupply Shipments
• All sites will receive an initial supply of brentuximab
vedotin upon activation in IXRS
• Drug dispensation via IXRS required at each patient
visit– Study drug will be assigned by lot number and quantity– IXRS will assign enough study drug for one specific patient
visit
• IXRS will use a threshold resupply model to calculate
subsequent shipments
• CRAs or study management team should be
contacted with any concerns regarding study drug
inventory14
CONFIDENTIAL
Supply ManagementAccountability
• CRAs should collect copy of the site’s guidelines/SOP for local
destruction of drug
• The study pharmacist is responsible for maintaining up-to date written
records of study drug inventory and destruction activities
• Sites should ensure the drug disposition is recorded comprehensively
(administration, return, and accountability) on the Overall Investigational
Product Inventory Logs (or equivalent)
• Sites may use their own drug logs if:– The required drug information is captured in the site logs– ICON and/or Millennium have approved the site logs for use– Copies can be collected during routine site monitoring and close out visits
• (REVIEW OF PHARMACY LOGS AND DOCUMENTS)
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CONFIDENTIAL 16
Supply ManagementAccountability (cont.)
• A Drug Accountability Record must be maintained for brentuximab vedotin to include:– The dates and quantities of drug received– Subject’s (identification number and/or initials or supply
number as applicable) for whom the investigational product was dispensed
– The date and quantity of investigational product dispensed – The initials of the dispenser at site
• At the end of the study, a final Investigational Product reconciliation statement must be completed by the Investigator or designee and provided to the Sponsor
CONFIDENTIAL
Supply ManagementDrug Return/Destruction
• Brentuximab vedotin destruction– Partially used/used vials:
• Should be disposed of in accordance with the institution’s standard drug disposal procedures
– Unused vials: • Once the CRA has performed study drug accountability and
reconciliation, the site should destroy in accordance with the institution’s standard drug disposal procedures (if written authorization has been provided from Millennium)
• If a site cannot destroy unused study drug, the assigned CRA may arrange return and destruction to Almac Clinical Services
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CONFIDENTIAL 181818
Manny FernandezGlobal and US Project ManagerTel: (210) 200-4119
Email:[email protected]
Lars Erik NilssonEU Clinical Trial Manager Tel: +46 8 5148 4717Email: [email protected]
Kimberly HartmanUS Clinical Trial Manager
Tel: 215-616-3038
Email: [email protected]
Tom OlsonAustralia Clinical Trial Manager Tel: +61 2 9859 3907Email: [email protected]
