thiotepa 100 MG Injection [Tepadina]

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.

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 cham

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 central nervous system toxicity occurs, discontinue administration of TEPADINA and provide supportive care. 5.7 Carcinogenicity Like many alkylating agents, thiotepa has been reported to be carcinogenic when administered to laboratory animals [see Nonclinical Toxicity ( 13.1 ) ] . Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. There is an increased risk of a secondary malignancy with use of TEPADINA. 5.8 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, TEPADINA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of TEPADINA in pregnant women. Thiotepa given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m 2 ), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m 2 ), based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21 mg/m 2 ), approximately equal to the maximum recommended human therapeutic dose, based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m 2 ), approximately two times the maximum recommended human therapeutic dose based on body-surface area. Advise pregnant women of the potential risk to the fetus [ see Use in Specific Populations ( 8.1 , 8.3 ) ] . Advise females of reproductive potential to use highly effective contraception during and after treatment with TEPADINA for 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with TEPADINA for 1 year after therapy [ see Use in Specific Populations ( 8.1 , 8.3 ) ] . 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

CONTRAINDICATIONS Thiotepa is contraindicated in patients with a known hypersensitivity (allergy) to this preparation. Therapy is probably contraindicated in cases of existing hepatic, renal, or bone-marrow damage. However, if the need outweighs the risk in such patients, thiotepa may be used in low dosage, and accompanied by hepatic, renal and hemopoietic function tests.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethyleneimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principle bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines. 12.2 Pharmacodynamics The exposure-response relationship for efficacy and safety has not been characterized. 12.3 Pharmacokinetics Absorption Thiotepa reached maximal concentrations close to the end infusion following an intravenous infusion. Distribution The binding of thiotepa to plasma proteins is approximately 10% to 20%. The mean volume of distribution (% coefficient of variation) of thiotepa was 30 L/m 2 (44%) or 1.2 L/kg (47%) following a single intravenous infusion of TEPADINA at a dose of 5 mg/kg over 3 hours in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m 2 as an intravenous bolus or infusion up to 4 hours, the mean volume of distribution of thiotepa ranged from 1.0 L/kg (30%) to 1.9 L/kg (17%). Elimination Following a single intravenous infusion over 3 hours of TEPADINA at a dose of 5 mg/kg in pediatric population, the estimated mean (% coefficient of variation) clearance of thiotepa was 0.58 L/hr/kg (60%) or 13.8 L/hr/m 2 (52%). The mean terminal elimination half-life was 1.7 hours (64%) for thiotepa and 4 hours (29%) for its major active metabolite, N,N',N''-triethylenephosphoramide (TEPA) in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m 2 as an intravenous bolus or infusion up to 4 hours, the mean thiotepa clearance ranged from 14.6 L/hr/m 2 (23%) to 27.9 L/hr/m 2 (69%). In adult population, the mean terminal elimination half-life ranged from 1.4 hours (7%) to 3.7 hours (14%) for thiotepa and from 4.9 hours to 17.6 hours (20%) for TEPA. Metabolism Thiotepa undergoes hepatic metabolism. In vitro data suggests that CYP3A4 and CYP2B6 may be responsible for the metabolism of thiotepa to TEPA, a major active metabolite. Excretion In adult and pediatric patients, urinary excretion of thiotepa accounted for less than 2% of the dose and TEPA accounted for 11% or less of the dose. Specific Populations Hepatic Impairment The clearance of thiotepa following a single TEPADINA dose of 5 mg/kg in pediatric population with mild hepatic impairment was similar to the clearance observed in patients with normal liver function administered thiotepa. The exposure (as measured by area under the curve (AUC)) of thiotepa increased by 1.6-fold and 1.8-fold following administration of multiple thiotepa doses of 7 mg/kg administered every 2 days with cyclophosphamide in two adult patients who had liver metastases with moderate hepatic impairment compared to the exposure observed in one patient with normal hepatic function . The effect of severe hepatic impairment on thiotepa exposure is unknown. Renal Impairment The exposure (as measured by AUC) of thiotepa increased by 1.4-fold and TEPA increased by 2.6-fold following administration of multiple doses of 120 mg/m 2 /day in one patient with moderate renal impairment (CLcr = 38 mL/min) administered cyclophosphamide plus thiotepa plus carboplatin, compared to exposure of thiotepa in patients with normal renal function.The effects of severe renal impairment or end-stage renal disease on thiotepa exposure are unknown. Drug Interactions The clinical relevance of in vitro inhibition of the cytochrome P450 enzymes described below is unknown, but it cannot be excluded that the systemic exposure of thiotepa or medicinal products that are substrates for these enzymes may be affected with concomitant administration with TEPADINA. Effect of Cytochrome P450 Modulators on Thiotepa In vitro data demonstrates that CYP3A4 and CYP2B6 inhibitors decrease the metabolism of thiotepa [see Drug Interactions (7.1) ] . Effect of Thiotepa on Cytochrome P450 2B6 In vitro data demonstrates that thiotepa inhibits CYP2B6. Effect of Thiotepa on Cyclophosphamide The administration of thiotepa 1.5 hours prior to intravenous cyclophosphamide in patients administered cyclophosphamide plus thiotepa plus carboplatin decreased the AUC of 4-hydroxycyclophosphamide by 26% and maximal concentrations of 4-hydroxycyclophosphamide by 62%, compared to administration of cyclophosphamide prior to thiotepa. 12.1 Mechanism of Action Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethyleneimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principle bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines.