TEPADINA

TEPADINA (thiotepa) is an alkylating agent. TEPADINA (thiotepa) for injection is supplied as a non-pyrogenic, sterile lyophilized white powder for intravenous, intracavitary, or intravesical use after reconstitution and dilution. TEPADINA is available In a single-dose vial containing 15 mg thiotepa. After reconstitution with 1.5 mL of Sterile Water for Injection, each mL contains 10 mg thiotepa; In a single-dose vial containing 100 mg thiotepa. After reconstitution with 10 mL of Sterile Water for Injection, each mL contains 10 mg thiotepa; In a single-dose multichamber flexible bag containing 200 mg thiotepa and 200 mL 0.9% Sodium Chloride Injection; In a single-dose multichamber flexible bag containing 400 mg thiotepa and 400 mL 0.9% Sodium Chloride Injection; Thiotepa is a synthetic product with antitumor activity. The chemical name for thiotepa is Tris(1-aziridinyl)phosphine sulfide. Thiotepa has the following structural formula: Thiotepa has the molecular formula C 6 H 12 N 3 PS, and a molecular weight of 189.23, and it appears as fine, white crystalline flakes, with a melting range of 52°C to 57°C. It is soluble in water and organic solvents. When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is unstable in acid medium. Thiotepa Structure

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. (1.1 , 14) For treatment of adenocarcinoma of the breast or ovary. (1.2) For controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities. (1.3) For treatment of superficial papillary carcinoma of the urinary bladder. (1.4) 1.1 Class 3 Beta-Thalassemia TEPADINA is 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 [see Clinical Studies ( 14 ) ] . 1.2 Adenocarcinoma of the Breast or Ovary TEPADINA is indicated for treatment of adenocarcinoma of the breast or ovary. 1.3 Malignant Effusions TEPADINA is indicated for controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities. 1.4 Superficial Papillary Carcinoma of the Urinary Bladder TEPADINA is indicated for treatment of superficial papillary carcinoma of the urinary bladder. 1.1 Class 3 Beta-Thalassemia TEPADINA is 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 [see Clinical Studies ( 14 ) ] . 1.2 Adenocarcinoma of the Breast or Ovary TEPADINA is indicated for treatment of adenocarcinoma of the breast or ovary. 1.3 Malignant Effusions TEPADINA is indicated for controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities. 1.4 Superficial Papillary Carcinoma of the Urinary Bladder TEPADINA is indicated for treatment of superficial papillary carcinoma of the urinary bladder.

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 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.

TEPADINA is contraindicated in: Patients with severe hypersensitivity to thiotepa [ see Warnings and Precautions (5.2) ] Concomitant use with live or attenuated vaccines [ see Warnings and Precautions (5.4) ] Hypersensitivity to the active substance (4) . Concomitant use with live or attenuated vaccines (4) .

The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [ see Warnings and Precautions ( 5.1 ) ] Infection [ see Warnings and Precautions ( 5.1 ) ] Hypersensitivity [ see Warnings and Precautions ( 5.2 ) ] Cutaneous Toxicity [ see Warnings and Precautions ( 5.3 ) ] Hepatic Veno-Occlusive Disease [ see Warnings and Precautions ( 5.5 ) ] Central Nervous System Toxicity [ see Warnings and Precautions (5.6) ] Carcinogenicity [ see Warnings and Precautions (5.7) ] The most common adverse reactions (incidence greater than 10%) are neutropenia, anemia, thrombocytopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated bilirubin, mucositis, cytomegalovirus infection, hemorrhage, diarrhea, hematuria and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ADIENNE at 844-668-3940 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions With the Preparative Regimen for Class 3 Beta-Thalassemia The safety of TEPADINA was evaluated by retrospective analysis of 76 pediatric patients with class 3 beta-thalassemia who underwent allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) using busulfan and cyclophosphamide with TEPADINA (n=25) or without TEPADINA (n=51) [ see Clinical Studies ( 14 ) ] . Adverse reactions were abstracted retrospectively from the medical records. Serious adverse events that occurred in the TEPADINA-treated and control cohort were, respectively: gastrointestinal hemorrhage (4% vs 2%), pneumonia (4% vs 0), seizure (4% vs 2%), subarachnoid hemorrhage (4% vs 0) and veno-occlusive disease (4% vs 2%). By 90 days after HSCT, grades 2 to 4 acute graft-versus-host disease was observed in 7 (28%) patients in the TEPADINA cohort and in 13 (26%) patients in the control cohort. By 1-year after transplantation, chronic graft-versus-host disease was observed in 8 (35%) of 23 evaluable patients in the TEPADINA cohort, and 7 (14%) of 49 evaluable patients in the control cohort. Adverse reactions occurring in at least 5% of patients treated with TEPADINA from start of the preparative regimen through 30 days after transplantation are shown in Table 3. Ta ble 3: Common Adverse Reactions (>5%) Occurring Through 30 Days After Transplantation In Patients With Class 3 Beta- Thalassemia Using Busulfan And Cyclophosphamide With Or Without TEPADINA in the Preparative Regimen Preparative Regimen of Busulfan and Cyclophosphamide With TEPADINA N=25 patients (%) Without TEPADINA N=51 patients (%) Adverse Reaction Any Grade Grade 3-5 1 Any Grade Grade 3-5 1 Mucositis 2 16 (64%) 4 (16%) 22 (43%) 1 (2%) Cytomegalovirus Infection 12 (48%) 0 15 (29%) 0 Hemorrhage 3 7 (28%) 2 (8%) 12 (24%) 3 (6%) Diarrhea 6 (24%) 0 7 (14%) 2 (4%) Hematuria 4 5 (20%) 0 10 (20%) 3 (6%) Rash 5 3 (12%) 0 11 (22%) 0 Intracranial Hemorrhage 6 2 (8%) 1 (4%) 0 0 Pseudomonas Infection 2 (8%) 0 0 0 1 Severe, life-threatening or fatal 2 Mucositis includes mouth hemorrhage, mucosal inflammation and stomatitis 3 Hemorrhage includes all hemorrhage terms 4 Hematuria includes cystitis hemorrhagic and hematuria 5 Rash includes dermatitis exfoliative, palmar erythema, rash, rash maculo-papular, rash pruritic and skin toxicity 6 Hemorrhage Intracranial includes hemorrhage intracranial and subarachnoid hemorrhage All patients in the TEPADINA-treated and control cohorts developed profound cytopenias, including neutropenia, anemia, thrombocytopenia. Table 4 shows the selected chemistry abnormalities that occurred from start of the preparative regimen through 30 days after transplantation. Table 4: Selected Laboratory Abnormalities Occurring Through 30 Days After Transplantation In Patients With Class 3 Beta- Thalassemia Using Busulfan And Cyclophosphamide With Or Without TEPADINA in the Preparative Regimen Preparative Regimen of Busulfan and Cyclophosphamide With TEPADINA N=25 patients (%) Without TEPADINA N=51 patients (%) Adverse Reaction Any Grade Grade 3-4 Any Grade Grade 3-4 Elevated alanine aminotransferase 22 (88%) 6 (24%) 49 (96%) 14 (27%) Elevated aspartate aminotransferase 20 (80%) 4 (16%) 45 (88%) 9 (18%) Elevated total bilirubin 20 (80%) 4 (16%) 39 (77%) 2 (4%) Adverse Reactions with Treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary, malignant effusions and superficial papillary carcinoma of the urinary bladder Gastrointestinal : Nausea, vomiting, abdominal pain, anorexia. General : Fatigue, weakness. Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumor tissue. Hypersensitivity Reactions : Allergic reactions - rash, urticaria, laryngeal edema, asthma, anaphylactic shock, wheezing. Local Reactions : Contact dermatitis, pain at the injection site. Neurologic : Dizziness, headache, blurred vision. Renal : Dysuria, urinary retention, chemical cystitis or hemorrhagic cystitis. Reproductive : Amenorrhea, interference with spermatogenesis. Respiratory : Prolonged apnea has been reported when succinylcholine was administered prior to surgery, following combined use of thiotepa and other anticancer agents. It was theorized that this was caused by decrease of pseudocholinesterase activity caused by the anticancer drugs. Skin : Dermatitis, alopecia. Skin depigmentation has been reported following topical use. Special Senses : Conjunctivitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of TEPADINA in preparative regimens prior to allogeneic or autologous hematopoietic progenitor (stem) cell transplantation (HSCT) in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders : Febrile bone marrow aplasia. Cardiac disorders : Bradycardia, cardiac failure congestive, cardio-respiratory arrest, pericardial effusion, pericarditis, right ventricular hypertrophy. Congenital, familial and genetic disorders : Aplasia. Ear and labyrinth disorders : Deafness. Eye disorders : Blindness, eyelid ptosis, papilledema, strabismus. Gastrointestinal disorders : Ascites, dysphagia, enterocolitis, gastritis, palatal disorder. General disorders and administration site conditions : Device related infection, gait disturbance, malaise, multi-organ failure, pain. Hepatobiliary disorders : Hepatomegaly. Immune system disorders : Bone marrow transplant rejection, immunosuppression. Infections and infestations: Acute sinusitis, bronchopulmonary aspergillosis, candida sepsis, enterococcal infection, Epstein-Barr virus infection, Escherichia sepsis, Fusarium infection, gastroenteritis, infection, lower respiratory tract infection fungal, lower respiratory tract infection viral, parainfluenza virus infection, Pneumonia legionella, relapsing fever, respiratory tract infection, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, systemic candida, urinary tract infection. Injury, poisoning and procedural complications : Refractoriness to platelet transfusion, subdural hematoma. Investigations : Coagulation test abnormal, hemoglobin decreased, Klebsiella test positive, nuclear magnetic resonance imaging brain abnormal, transaminases increased, weight increased. Metabolism and nutrition disorders : Hyponatremia. Neoplasms benign, malignant and unspecified (incl. cysts and polyps) : Breast cancer metastatic, central nervous system lymphoma, leukemia recurrent, lymphoma, malignant neoplasm progression, metastatic neoplasm, post transplant lymphoproliferative disorder. Nervous system disorders : Aphasia, brain injury, bulbar palsy, central nervous system lesion, cerebral microangiopathy, cerebral ventricle dilatation, cerebrovascular accident, cognitive disorder, convulsion, coordination abnormal, encephalitis, encephalopathy, hemiplegia, hypotonia, leukoencephalopathy, memory impairment, motor dysfunction, neurotoxicity, quadriparesis, speech disorder, tremor, VIIth nerve paralysis, white matter lesion. Psychiatric disorders : Delirium, depression, disorientation, suicidal ideation. Renal and urinary disorders : Renal failure, nephropathy toxic. Respiratory, thoracic and mediastinal disorders : Acute respiratory distress, aspiration, dyspnea exertional, interstitial lung disease, lung disorder, pneumonitis, pulmonary arteriopathy, pulmonary sepsis, pulmonary veno-occlusive disease, respiratory distress, respiratory failure, pulmonary hypertension. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome and toxic epidermal necrolysis. Vascular disorders : Capillary leak syndrome. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions With the Preparative Regimen for Class 3 Beta-Thalassemia The safety of TEPADINA was evaluated by retrospective analysis of 76 pediatric patients with class 3 beta-thalassemia who underwent allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) using busulfan and cyclophosphamide with TEPADINA (n=25) or without TEPADINA (n=51) [ see Clinical Studies ( 14 ) ] . Adverse reactions were abstracted retrospectively from the medical records. Serious adverse events that occurred in the TEPADINA-treated and control cohort were, respectively: gastrointestinal hemorrhage (4% vs 2%), pneumonia (4% vs 0), seizure (4% vs 2%), subarachnoid hemorrhage (4% vs 0) and veno-occlusive disease (4% vs 2%). By 90 days after HSCT, grades 2 to 4 acute graft-versus-host disease was observed in 7 (28%) patients in the TEPADINA cohort and in 13 (26%) patients in the control cohort. By 1-year after transplantation, chronic graft-versus-host disease was observed in 8 (35%) of 23 evaluable patients in the TEPADINA cohort, and 7 (14%) of 49 evaluable patients in the control cohort. Adverse reactions occurring in at least 5% of patients treated with TEPADINA from start of the preparative regimen through 30 days after transplantation are shown in Table 3. Ta ble 3: Common Adverse Reactions (>5%) Occurring Through 30 Days After Transplantation In Patients With Class 3 Beta- Thalassemia Using Busulfan And Cyclophosphamide With Or Without TEPADINA in the Preparative Regimen Preparative Regimen of Busulfan and Cyclophosphamide With TEPADINA N=25 patients (%) Without TEPADINA N=51 patients (%) Adverse Reaction Any Grade Grade 3-5 1 Any Grade Grade 3-5 1 Mucositis 2 16 (64%) 4 (16%) 22 (43%) 1 (2%) Cytomegalovirus Infection 12 (48%) 0 15 (29%) 0 Hemorrhage 3 7 (28%) 2 (8%) 12 (24%) 3 (6%) Diarrhea 6 (24%) 0 7 (14%) 2 (4%) Hematuria 4 5 (20%) 0 10 (20%) 3 (6%) Rash 5 3 (12%) 0 11 (22%) 0 Intracranial Hemorrhage 6 2 (8%) 1 (4%) 0 0 Pseudomonas Infection 2 (8%) 0 0 0 1 Severe, life-threatening or fatal 2 Mucositis includes mouth hemorrhage, mucosal inflammation and stomatitis 3 Hemorrhage includes all hemorrhage terms 4 Hematuria includes cystitis hemorrhagic and hematuria 5 Rash includes dermatitis exfoliative, palmar erythema, rash, rash maculo-papular, rash pruritic and skin toxicity 6 Hemorrhage Intracranial includes hemorrhage intracranial and subarachnoid hemorrhage All patients in the TEPADINA-treated and control cohorts developed profound cytopenias, including neutropenia, anemia, thrombocytopenia. Table 4 shows the selected chemistry abnormalities that occurred from start of the preparative regimen through 30 days after transplantation. Table 4: Selected Laboratory Abnormalities Occurring Through 30 Days After Transplantation In Patients With Class 3 Beta- Thalassemia Using Busulfan And Cyclophosphamide With Or Without TEPADINA in the Preparative Regimen Preparative Regimen of Busulfan and Cyclophosphamide With TEPADINA N=25 patients (%) Without TEPADINA N=51 patients (%) Adverse Reaction Any Grade Grade 3-4 Any Grade Grade 3-4 Elevated alanine aminotransferase 22 (88%) 6 (24%) 49 (96%) 14 (27%) Elevated aspartate aminotransferase 20 (80%) 4 (16%) 45 (88%) 9 (18%) Elevated total bilirubin 20 (80%) 4 (16%) 39 (77%) 2 (4%) Adverse Reactions with Treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary, malignant effusions and superficial papillary carcinoma of the urinary bladder Gastrointestinal : Nausea, vomiting, abdominal pain, anorexia. General : Fatigue, weakness. Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumor tissue. Hypersensitivity Reactions : Allergic reactions - rash, urticaria, laryngeal edema, asthma, anaphylactic shock, wheezing. Local Reactions : Contact dermatitis, pain at the injection site. Neurologic : Dizziness, headache, blurred vision. Renal : Dysuria, urinary retention, chemical cystitis or hemorrhagic cystitis. Reproductive : Amenorrhea, interference with spermatogenesis. Respiratory : Prolonged apnea has been reported when succinylcholine was administered prior to surgery, following combined use of thiotepa and other anticancer agents. It was theorized that this was caused by decrease of pseudocholinesterase activity caused by the anticancer drugs. Skin : Dermatitis, alopecia. Skin depigmentation has been reported following topical use. Special Senses : Conjunctivitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of TEPADINA in preparative regimens prior to allogeneic or autologous hematopoietic progenitor (stem) cell transplantation (HSCT) in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders : Febrile bone marrow aplasia. Cardiac disorders : Bradycardia, cardiac failure congestive, cardio-respiratory arrest, pericardial effusion, pericarditis, right ventricular hypertrophy. Congenital, familial and genetic disorders : Aplasia. Ear and labyrinth disorders : Deafness. Eye disorders : Blindness, eyelid ptosis, papilledema, strabismus. Gastrointestinal disorders : Ascites, dysphagia, enterocolitis, gastritis, palatal disorder. General disorders and administration site conditions : Device related infection, gait disturbance, malaise, multi-organ failure, pain. Hepatobiliary disorders : Hepatomegaly. Immune system disorders : Bone marrow transplant rejection, immunosuppression. Infections and infestations: Acute sinusitis, bronchopulmonary aspergillosis, candida sepsis, enterococcal infection, Epstein-Barr virus infection, Escherichia sepsis, Fusarium infection, gastroenteritis, infection, lower respiratory tract infection fungal, lower respiratory tract infection viral, parainfluenza virus infection, Pneumonia legionella, relapsing fever, respiratory tract infection, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, systemic candida, urinary tract infection. Injury, poisoning and procedural complications : Refractoriness to platelet transfusion, subdural hematoma. Investigations : Coagulation test abnormal, hemoglobin decreased, Klebsiella test positive, nuclear magnetic resonance imaging brain abnormal, transaminases increased, weight increased. Metabolism and nutrition disorders : Hyponatremia. Neoplasms benign, malignant and unspecified (incl. cysts and polyps) : Breast cancer metastatic, central nervous system lymphoma, leukemia recurrent, lymphoma, malignant neoplasm progression, metastatic neoplasm, post transplant lymphoproliferative disorder. Nervous system disorders : Aphasia, brain injury, bulbar palsy, central nervous system lesion, cerebral microangiopathy, cerebral ventricle dilatation, cerebrovascular accident, cognitive disorder, convulsion, coordination abnormal, encephalitis, encephalopathy, hemiplegia, hypotonia, leukoencephalopathy, memory impairment, motor dysfunction, neurotoxicity, quadriparesis, speech disorder, tremor, VIIth nerve paralysis, white matter lesion. Psychiatric disorders : Delirium, depression, disorientation, suicidal ideation. Renal and urinary disorders : Renal failure, nephropathy toxic. Respiratory, thoracic and mediastinal disorders : Acute respiratory distress, aspiration, dyspnea exertional, interstitial lung disease, lung disorder, pneumonitis, pulmonary arteriopathy, pulmonary sepsis, pulmonary veno-occlusive disease, respiratory distress, respiratory failure, pulmonary hypertension. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome and toxic epidermal necrolysis. Vascular disorders : Capillary leak syndrome.

7.1 Effect of Cytochrome CYP3A Inhibitors and Inducers In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite TEPA. Avoid co-administration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with TEPADINA due to the potential effects on efficacy and toxicity [see Clinical Pharmacology ( 12.3 ) ] . Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions. 7.2 Effect of TEPADINA on Cytochrome CYP2B6 Substrates In vitro studies suggest that thiotepa inhibits CYP2B6. TEPADINA may increase the exposure of drugs that are substrates of CYP2B6 in patients; however, the clinical relevance of this in vitro interaction is unknown [see Clinical Pharmacology ( 12.3 ) ] . The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4-hydroxycyclophosphamide; the effect appears sequence dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours prior to the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide [see Clinical Pharmacology ( 12.3 ) ] . The reduction in 4-hydroxycyclophosphamide levels may potentially reduce efficacy of cyclophosphamide treatment. 7.1 Effect of Cytochrome CYP3A Inhibitors and Inducers In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite TEPA. Avoid co-administration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with TEPADINA due to the potential effects on efficacy and toxicity [see Clinical Pharmacology ( 12.3 ) ] . Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions. 7.2 Effect of TEPADINA on Cytochrome CYP2B6 Substrates In vitro studies suggest that thiotepa inhibits CYP2B6. TEPADINA may increase the exposure of drugs that are substrates of CYP2B6 in patients; however, the clinical relevance of this in vitro interaction is unknown [see Clinical Pharmacology ( 12.3 ) ] . The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4-hydroxycyclophosphamide; the effect appears sequence dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours prior to the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide [see Clinical Pharmacology ( 12.3 ) ] . The reduction in 4-hydroxycyclophosphamide levels may potentially reduce efficacy of cyclophosphamide treatment.