TEPADINA

2 DOSAGE AND ADMINISTRATION The recommended dosage of TEPADINA for class 3 beta-thalassemia is two administrations of 5 mg/kg given by intravenous infusion approximately 12 hours apart on Day -6 before allogeneic HSCT in conjunction with high-dose busulfan and cyclophosphamide. (2.1) The recommended dosage of TEPADINA for treatment of adenocarcinoma of the breast or ovary is 0.3 mg/kg to 0.4 mg/kg by intravenous infusion. (2.1) The recommended dosage of TEPADINA for treatment of malignant effusions is 0.6 mg/kg to 0.8 mg/kg intracavitary. (2.1) The recommended dosage of TEPADINA for treatment of superficial papillary carcinoma of the urinary bladder is 60 mg in 30 mL to 60 mL of 0.9% Sodium Chloride Injection into the bladder by catheter. (2.1) See Full Prescribing Information for preparation and administration instructions. (2.2 , 2.3) 2.1 Recommended Dosage Class 3 Beta-Thalassemia The recommended dosage of TEPADINA in pediatric patients is two administrations of 5 mg/kg given by intravenous infusion approximately 12 hours apart on Day -6 before allogeneic HSCT in conjunction with high-dose busulfan and cyclophosphamide as outlined in Table 1. See Prescribing Information for cyclophosphamide and busulfan for information on these drugs. Table 1: Dosage Regimen For Allogeneic HSCT In Pediatric Patients With Class 3 Beta-Thalassemia Treatment Day prior to transplantation Day ‑10 Day ‑9 Day ‑8 Day ‑7 Day ‑6 Day ‑5 Day ‑4 Day ‑3 Day ‑2 Day ‑1 Day 0 Busulfan intravenous weight-based dose * ▲ ▲ ▲ ▲ TEPADINA intravenous 5 mg/kg twice ▲ Cyclophosphamide intravenous 40 mg/kg/day ▲ ▲ ▲ ▲ Stem cell Infusion ▲ *Busulfan intravenous weight-based dose: 1 mg/kg every 6 hours for patients less than 9 kg; 1.2 mg/kg every 6 hours for patients 9 kg to 16 kg; 1.1 mg/kg every 6 hours for patients 16.1 kg to 23 kg; 0.95 mg/kg every 6 hours for patients 23.1 kg to 34 kg; 0.8 mg/kg every 6 hours for patients more than 34 kg. Infuse TEPADINA via a central venous catheter over 3 hours using an infusion set equipped with a 0.2 micron in-line filter. Prior to and following each infusion, flush the catheter with approximately 5 mL of 0.9% Sodium Chloride Injection. TEPADINA is excreted through the skin of patients receiving high-dose therapy. Take precautions to prevent skin toxicity [ see Warnings and Precautions ( 5.3 ) ] . Adenocarcinoma of the Breast or Ovary The recommended dosage of TEPADINA for treatment of adenocarcinoma of the breast or ovary is 0.3 mg/kg to 0.4 mg/kg by intravenous infusion. Doses should be given at 1 to 4 week intervals. Initially the higher dose in the given range is commonly administered. The maintenance dose should be adjusted weekly on the basis of pre-treatment control blood counts and subsequent blood counts. Maintenance dosages should not be administered more frequently than weekly. Malignant Effusions The recommended dosage of TEPADINA for treatment of malignant effusions is 0.6 mg/kg to 0.8 mg/kg intracavitary. Administration is usually effected through the same tubing which is used to remove the fluid from the cavity involved. Doses should be given at 1 to 4 week intervals. Initially the higher dose in the given range is commonly administered. The maintenance dose should be adjusted weekly on the basis of pre-treatment control blood counts and subsequent blood counts. Maintenance dosages should not be administered more frequently than weekly. Superficial Papillary Carcinoma of the Urinary Bladder The recommended dosage of TEPADINA for treatment of superficial papillary carcinoma of the urinary bladder is 60 mg in 30 mL to 60 mL of 0.9% Sodium Chloride Injection into the bladder by catheter. The solution should be retained for 2 hours. If the patient finds it impossible to retain 60 mL for 2 hours, the dose may be given in a volume of 30 mL. The patient may be repositioned every 15 minutes for maximum area contact. The usual course of treatment is once a week for 4 weeks. The course may be repeated if necessary, but second and third courses must be given with caution since bone-marrow depression may be increased. 2.2 Preparation Instructions TEPADINA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Use appropriate aseptic technique. Preparation from the Vial Reconstitution of the vial Reconstitute each TEPADINA vial with Sterile Water for Injection using the volumes described in Table 2. Table 2: Reconstitution Volumes for the Vials Strength Amount of Sterile Water for Injection required for reconstitution Final concentration 15 mg vial 1.5 mL 10 mg/mL 100 mg vial 10 mL 10 mg/mL Mix the vial by repeated inversions until the powder is completely dissolved. Visually inspect reconstituted solution in the vial for particulate matter and discoloration. The reconstituted solution may occasionally show opalescence. Use the reconstituted solution immediately. If not used immediately, store the reconstituted solution in the vial refrigerated at 2°C to 8°C (36°F to 46°F), for up to 80 hours. Dilution of the reconstituted vial into an infusion bag Withdraw the required volume of the reconstituted solution from the TEPADINA vial. Discard any unused portion. Transfer the reconstituted solution into an intravenous bag containing 0.9% Sodium Chloride Injection to obtain a final concentration between 0.5 mg/mL and 1 mg/mL. Gently mix the intravenous bag by slowly inverting the bag. Use the diluted solution immediately. If the diluted solution is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours or room temperature at 25°C (77°F) for up to 6 hours. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use TEPADINA diluted solutions only if free of visible particulate matter. For intravenous administration of high doses in the preparative regimen for allogeneic HSCT for beta thalassemia, administer by intravenous infusion via central venous catheter over 3 hours using an infusion set equipped with 0.2 micron filter. For intravesicular administration into the bladder by catheter, see further instructions in Dosage and Administration Section 2.1. For all other indications, see further instructions in Dosage and Administration Section 2.1. Preparation from the Multichamber Flexible Bag See the Instructions for Use in Subsection 2.3 for illustrated steps for preparation and administration of TEPADINA from the multichamber flexible bag . Activation of the TEPADINA Multichamber Flexible Bag Activate the multichamber flexible bag by pressing firmly and applying uniform pressure with the palms of your overlapped hands until the peel seal is broken. Mix gently until the reconstituted solution is completely dissolved. Administer TEPADINA immediately after reconstitution of the multichamber flexible bag. If not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 168 hours or at room temperature at 20°C to 25°C (68°F to 77°F) up to 56 hours. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Solution should be colorless and without particulate matter. After activation, the resultant concentration is 1 mg/mL. 200 mg or 400 mg dose can be directly administered from the multichamber flexible bag after activation. For doses other than 200 mg or 400 mg, withdraw the patient-specific dose from the multichamber flexible bag for transfer to a separate empty bag for administration. No further dilution is necessary. Administer using a 0.2 micron filter. 2.3 Instructions for Use of the Multichamber Flexible Bag: Multichamber Flexible Bag Use Instructions Figure A 1 - Overwrap Notch Figure B 2 – NEVER use this port 3 – Luer Port 4 – Twist off Port 5 – Label Area 6 – Peel Seal (Must break to activate) 7 – Hole (For hanging the bag) 8 – Diluent chamber 9 – Lyophilized powder chamber TEPADINA ® 200 mg TEPADINA ® 400 mg 1 – REMOVE OVERWRAP a) Place bag on a clean, stable surface before opening. b) Tear from overwrap notch, located close to the ports (Figure A – point 1). c) Tear short sides open to access the inner bag as per Figure C. Figure C d) Remove the multichamber flexible bag from the aluminum overwrap and unfold the bag Figure D. Figure D 2 - INSPECT BAG PRIOR TO ACTIVATION 3 – ACTIVATE THE BAG Place bag on a clean, stable surface with the ports pointing away from you, as per Figure E . Check that there are no liquid or product leakages from the connection ports 2, 3, 4 and from the chambers 8, 9. Check the integrity of peel seal 6 , verifying the absence of liquid in the chamber 9 . Figure E TEPADINA 200 mg ® TEPADINA ® 400 mg Overlap your hands, on the lower portion of chamber 8 (as per Figure F ). Press firmly and apply uniform pressure until peel seal 6 is completely activated (it may take up to 5 seconds of continued pressure to break the peel seal 6 ). Figure F TEPADINA 200 mg ® TEPADINA ® 400 mg BAG BEFORE ACTIVATION BAG AFTER ACTIVATION Figure G Figure H Do NOT squeeze. Figure I 4 – INSPECT BAG TO CONFIRM ACTIVATION Check the peel seal 6 is now completely activated. Chamber 8 and 9 are merged. If the bag is not activated, refer to Step 3. Figure J Mix gently until complete dissolution of product. After activation, the resultant concentration is 1 mg/mL. A dose of 200 mg or 400 mg may be directly infused from the bag (see Step 6). For doses less than 200 mg or 400 mg see Step 5. Figure K 5 – DOSE PREPARATION – for doses less than 200 mg or 400 mg withdraw the patient-specific dose from the TEPADINA® multichamber flexible bag and transfer to an appropriately-sized, empty, sterile bag for intravenous infusion. Identify the Luer Port 3 if withdrawing a dose is needed. Remove the plastic cap from Luer Port. Figure L Screw the luer lock device as per Figure M. Do not use unproper non luer lock devices on port 3 . Figure M Ensure that the connection is fully seated and tighten. Withdraw the desired dose from TEPADINA® bag. This may require multiple graduated syringes depending on the desired dose. Unscrew each syringe counter-clockwise when finished. Figure N Replace the plastic cap on the Luer-Lock port 3. Attach a needle or an appropriate closed-system transfer device to each syringe containing thiotepa solution and transfer the contents to an appropriately-sized, empty, sterile bag for intravenous infusion. Discard the unused portion of the TEPADINA® bag. Follow applicable special handling and disposal procedures. 6 – CONNECTION for administration of 200 mg or 400 mg - The infusion set may be connected to the bag through either the spike connector OR the luer connector. OPTION A – SPIKE CONNECTION Identify Twist off port 4 . Twist off the plastic cap before inserting the spike. Figure O Insert the spike connector. Figure P OPTION B– LUER CONNECTION Select luer cap port 3 . Remove the plastic cap from luer port 3 before connecting the luer connector. Figure Q Insert the luer connector. Figure R Ensure that the connection is fully seated and tighten. 7 – HANG THE BAG Hang the bag by the hole 7 . Figure S figure a figure b figure b-400mg bag figure c figure d figure e figure e-400mg bag figure f figure f-400mg bag figure g figure h figure I figure j figure k figure L figure m figure N figure O figure P figure Q figure R figure S

See official label

1 INDICATIONS AND USAGE TEPADINA (thiotepa) is an alkylating drug indicated: To reduce the risk of graft rejection when used in conjunction with high-dose busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) for pediatric patients with class 3 beta-thalassemia.