TEPADINA

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. (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.

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 s…

5 WARNINGS AND PRECAUTIONS Cutaneous toxicity: Cleanse skin at least twice daily through 48 hours after the last dose of TEPADINA. (5.3) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.8) 5.1 Myelosuppression The consequence of treatment with high doses of TEPADINA together with other chemotherapy at the recommended dose and schedule in the preparative regimen for class 3 beta- thalassemia is profound myelosuppression occurring in all patients. Do not begin the preparative regimen if a stem cell donor is not available. Monitor complete blood counts, and provide supportive care for infections, anemia and thrombocytopenia until there is adequate hematopoietic recovery. For patients receiving TEPADINA for treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary, malignant effusions and superficial papillary carcinoma of the urinary bladder, if the bone marrow has been compromised by prior irradiation or chemotherapy, or is recovering from chemotherapy, the risk of severe myelosuppression with TEPADINA may be increased. Perform periodic complete blood counts during the course of treatment with TEPADINA. Provide supportive care for infections, bleeding, and symptomatic anemia [ see Adverse Reactions (6.1) ] . 5.2 Hypersensitivity Clinically significant hypersensitivity reactions, including anaphylaxis, have occurred following administration of TEPADINA. If anaphylactic or other clinically significant allergic reaction occurs, discontinue treatment with TEPADINA, initiate appropriate therapy, and monitor until signs and symptoms resolve [see Contraindications ( 4 ) , Adverse Reactions ( 6.1 ) ] . 5.3 Cutaneous Toxicity TEPADINA and/or its active metabolites may be excreted in part via skin patients receiving high-dose therapy. Treatment with TEPADINA may cause skin discoloration, pruritus, blistering, desquamation, and peeling that may be more severe in the groin, axillae, skin folds, in the neck area, and under dressings. Instruct patients to shower or bathe with water at least twice daily through 48 hours after administration of TEPADINA. Change occlusive dressing and clean the covered skin at least twice daily through 48 hours after administration of TEPADINA. Change bed sheets daily during treatment. Skin reactions associated with accidental exposure to TEPADINA may also occur. Wash the skin thoroughly with soap and water in case TEPADINA solution contacts the skin. Flush mucous membranes in case of TEPADINA contact with mucous membranes. 5.4 Concomitant Use of Live and Attenuated Vaccines Do not administer live or attenuated viral or bacterial vaccines to a patient treated with TEPADINA until the immunosuppressive effects have resolved. 5.5 Hepatic Veno-Occlusive Disease Hepatic veno-occlusive disease may occur in patients who have received high-dose TEPADINA in conjunction with busulfan and cyclophosphamide [ see Adverse Reactions (6.1) ]. Monitor by physical examination, serum transaminases and bilirubin daily through BMT Day +28, and provide supportive care to patients who develop hepatic veno-occlusive disease. 5.6 Central Nervous System Toxicity Fatal encephalopathy has occurred in patients treated with high doses of thiotepa. Other central nervous system toxicities, such as headache, apathy, psychomotor retardation, disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence, seizures, coma, inappropriate behaviour and forgetfulness have been reported to occur in a dose-dependent manner during or shortly after administration of high-dose thiotepa. In pediatric patients treated with TEPADINA at the recommended dose in combination with busulfan and cyclophosphamide, 8% developed central nervous system toxicity (seizures and intracranial hemorrhage). Do not exceed the recommended dose of TEPADINA. If severe or life-threatening centr…

4 CONTRAINDICATIONS 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) .

7 DRUG INTERACTIONS 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.

6 ADVERSE REACTIONS 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 …